Steep Rebound of Chloroquine-Sensitive<i>Plasmodium falciparum</i>in Zimbabwe

Mharakurwa, Sungano; Matsena-Zingoni, Zvifadzo; Mudare, Nobert; Matimba, Charmaine; Gara, Tanatswa Xuxa; Makuwaza, Aramu; Maponga, Gladys; Munyati, Shungu; Gwanzura, Lovemore; Mutambu, Susan; Mason, Peter R.; Tamaki, Kunihiko; Midzi, Nicholas; Moss, William J.; Ippolito, Matthew M.

doi:10.1093/infdis/jiaa368

Cited by 11 publications

(11 citation statements)

References 15 publications

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“…No mutations were observed in the 72-76 codons of the Pfcrt gene, which is consistent with several studies conducted in Madagascar [38,39]. Mutations in this gene, especially the 76T codon, were associated with resistance to chloroquine and amodiaquine in several African countries which then reported the "return" of chloroquine-susceptible parasites with wildtype alleles, as early as 10 years after chloroquine withdrawal [40,41]. Madagascar is among countries not recommending the use of chloroquine for treatment of malaria for over ten years due to high rates of chloroquine treatment failures.…”

Section: Discussionsupporting

confidence: 88%

Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for Uncomplicated Plasmodium Falciparum Malaria in Madagascar, 2018

Dentinger¹,

Rakotomanga

Rakotondrandriana

et al. 2021

Preprint

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Background: Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated Plasmodium falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of antimalarial resistance.Methods: Children aged six months through 14 years with uncomplicated P. falciparum malaria and a parasitemia of 1,000—100,000 parasites/µl determined by microscopy were enrolled from May—September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring antimalarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt, and pfmdr1 genes were conducted.Results: Of 344 patients enrolled, 164/170 (96%) receiving ASAQ and 170/174 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100–100) and 95% (95% CI 91–100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97–100) in Ankazomborona and 84% (95% CI 76–92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100–100) and 97% (95% CI 94–100%) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99–100) in Ankazomborona and 96% (95% CI 91–100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutations associated with artemisinin resistance were observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184, and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72–76. Conclusion: PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. We did not observe any genetic evidence of resistance to artemisinin, consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

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Section: Discussionsupporting

confidence: 88%

Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for Uncomplicated Plasmodium Falciparum Malaria in Madagascar, 2018

Dentinger¹,

Rakotomanga

Rakotondrandriana

et al. 2021

Preprint

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“…No mutations were observed in the 72–76 codons of the pfcrt gene, which is consistent with several studies conducted in Madagascar [ 35 , 36 ]. Mutations in this gene, especially the 76 T codon, were associated with resistance to chloroquine and amodiaquine in several African countries which then reported the “return” of chloroquine-susceptible parasites with wild type alleles, as early as 10 years after chloroquine withdrawal [ 37 , 38 ]. Madagascar is among countries not recommending the use of chloroquine for treatment of malaria in over 10 years due to high rates of chloroquine treatment failures.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of artesunate-amodiaquine and artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria in Madagascar, 2018

Dentinger

Rakotomanga

Rakotondrandriana³

et al. 2021

Malar J

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Background Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of anti-malarial resistance. Methods Children aged six months to 14 years with uncomplicated falciparum malaria and a parasitaemia of 1000–100,000 parasites/µl determined by microscopy were enrolled from May–September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring anti-malarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms at their respective sites. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt and pfmdr1 genes were conducted. Results Of 344 patients enrolled, 167/172 (97%) receiving ASAQ and 168/172 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100–100) and 95% (95% CI 91–100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97–100) in Ankazomborona and 83% (95% CI 76–92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100–100) and 98% (95% CI 95–100) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99–100) in Ankazomborona and 95% (95% CI 91–100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutation associated with artemisinin resistance was observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184 and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72–76. Conclusion PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. No genetic evidence of resistance to artemisinin was observed, which is consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

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“…Evidence of genotypic and phenotypic correlates of resistance to one or more ACT components is beginning to emerge in sub-Saharan Africa, South Asia, and South America including a recent report from Rwanda where P. falciparum kelch13 (pfk13) R561H, P574L, and C469Y alleles-previously linked to a delayed clearance phenotype [60•]-were detected [33, 40, 61••, 62•, 63•]. Resistance to the antifolates remains widespread, while reversion of CQresistant parasite populations to the CQ-susceptible wild type followed in the wake of withdrawing CQ from national formularies in eastern and central-southern Africa [64][65][66][67][68][69][70][71].…”

Section: Historical Origins and Present Distribution Of Drug-resistant Malariamentioning

confidence: 99%

Antimalarial Drug Resistance and Implications for the WHO Global Technical Strategy

et al. 2021

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Purpose of Review Five years have passed since the World Health Organization released its Global Technical Strategy for Malaria (GTS). In that time, progress against malaria has plateaued. This review focuses on the implications of antimalarial drug resistance for the GTS and how interim progress in parasite genomics and antimalarial pharmacology offer a bulwark against it. Recent Findings For the first time, drug resistance–conferring genes have been identified and validated before their global expansion in malaria parasite populations. More efficient methods for their detection and elaboration have been developed, although low-density infections and polyclonality remain a nuisance to be solved. Clinical trials of alternative regimens for multidrug-resistant malaria have delivered promising results. New agents continue down the development pipeline, while a nascent infrastructure in sub-Saharan Africa for conducting phase I trials and trials of transmission-blocking agents has come to fruition after years of preparation. Summary These and other developments can help inform the GTS as the world looks ahead to the next two decades of its implementation. To remain ahead of the threat that drug resistance poses, wider application of genomic-based surveillance and optimization of existing and forthcoming antimalarial drugs are essential.

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Steep Rebound of Chloroquine-SensitivePlasmodium falciparumin Zimbabwe

Cited by 11 publications

References 15 publications

Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for Uncomplicated Plasmodium Falciparum Malaria in Madagascar, 2018

Efficacy of Artesunate-Amodiaquine and Artemether-Lumefantrine for Uncomplicated Plasmodium Falciparum Malaria in Madagascar, 2018

Efficacy of artesunate-amodiaquine and artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria in Madagascar, 2018

Antimalarial Drug Resistance and Implications for the WHO Global Technical Strategy

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