Continued Low Efficacy of Artemether-Lumefantrine in Angola in 2019

Dimbu, Pedro Rafael; Horth, Roberta; Cândido, Ana Luísa Micolo; Ferreira, Carolina Miguel; Caquece, Felismina; Garcia, Luzala Elisabeth Armando; André, Kialanda; Pembele, García Nazaré; Jandondo, Domingos; Bondo, Belmira José; Andrade, Benjamin Nieto; Labuda, Sarah M; León, Gabriel Ponce de; Kelley, Julia; Patel, Dhruviben; Svigel, Samaly S.; Talundzic, Eldin; Lucchi, Naomi W.; Morais, José; Fortes, Filomeno; Martins, José Franco; Pluciński, Mateusz M.

doi:10.1128/aac.01949-20

Cited by 46 publications

(39 citation statements)

References 20 publications

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“…However, when accounting for a 95% confidence interval, the 86.0–95.9% PCR-corrected efficacy range of AL indicates that continued frequent efficacy monitoring of this drug is warranted in Mali. These findings are not unlike those from Uganda [ 35 ], Angola [ 36 ], and Burkina Faso [ 37 ], which have also shown AL not performing as well as other artemisinin-based combinations, such as ASAQ and DP. Similar to the AL day 28 uncorrected efficacy of 83.4% in this study, two other studies from Mali examining day 28 uncorrected efficacy reported results of 83.8% and 84.5% [ 33 , 34 ] and the study performed in Burkina Faso by Tinto & al, gave 58.4% for ASAQ and 46.1% for AL [ 32 ].…”

Section: Discussioncontrasting

confidence: 68%

Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

Diarra

Koné

Sangaré

et al. 2021

Malar J

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Background The current first-line treatments for uncomplicated malaria recommended by the National Malaria Control Programme in Mali are artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ). From 2015 to 2016, an in vivo study was carried out to assess the clinical and parasitological responses to AL and ASAQ in Sélingué, Mali. Methods Children between 6 and 59 months of age with uncomplicated Plasmodium falciparum infection and 2000–200,000 asexual parasites/μL of blood were enrolled, randomly assigned to either AL or ASAQ, and followed up for 42 days. Uncorrected and PCR-corrected efficacy results at days 28 and 42. were calculated. Known markers of resistance in the Pfk13, Pfmdr1, and Pfcrt genes were assessed using Sanger sequencing. Results A total of 449 patients were enrolled: 225 in the AL group and 224 in the ASAQ group. Uncorrected efficacy at day 28 was 83.4% (95% CI 78.5–88.4%) in the AL arm and 93.1% (95% CI 89.7–96.5%) in the ASAQ arm. The per protocol PCR-corrected efficacy at day 28 was 91.0% (86.0–95.9%) in the AL arm and 97.1% (93.6–100%) in the ASAQ arm. ASAQ was significantly (p < 0.05) better than AL for each of the aforementioned efficacy outcomes. No mutations associated with artemisinin resistance were identified in the Pfk13 gene. Overall, for Pfmdr1, the N86 allele and the NFD haplotype were the most common. The NFD haplotype was significantly more prevalent in the post-treatment than in the pre-treatment isolates in the AL arm (p < 0.01) but not in the ASAQ arm. For Pfcrt, the CVIET haplotype was the most common. Conclusions The findings indicate that both AL and ASAQ remain effective for the treatment of uncomplicated malaria in Sélingué, Mali.

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Section: Discussioncontrasting

confidence: 68%

Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

Diarra

Koné

Sangaré

et al. 2021

Malar J

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“…Mutations in the pfmdr1 gene have been shown to play a signi cant role in parasites' tolerance to some antimalarials such as chloroquine, amodiaquine, artemisinin derivatives and lumefantrine; N86 wild type allele is implicated in decreased sensitivity to lumefantrine while the 86Y mutant allele, in combination with mutations in the pfcrt gene, is associated with decreased sensitivity to chloroquine and amodiaquine [33][34][35]. Pfmdr1 results in our study revealed a high prevalence of the N86 allele (NFD and NYD haplotypes), a nding seen recently in other countries throughout Southern and East Africa [7,36,37]. In six sites in Madagascar in 2006, the NFD and NYD haplotypes were observed in only 21.8% and 8.0% samples, respectively, although these frequencies increased to 30.0% and 14.6% just one year later [38].…”

Section: Discussionsupporting

confidence: 66%

“…For AL, however, no recent studies to evaluate therapeutic e cacy have been done in Madagascar. Evidence of reduced AL e cacy has been described in SSA [10][11][12]; given that it is the second-line antimalarial in Madagascar, and has at times been used as the rst-line treatment due to shortages of ASAQ, describing its e cacy in Madagascar is important.…”

Section: Introductionmentioning

confidence: 99%

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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“…We obtained previously collected and publicly available microsatellite genotyping data from five studies with 13 trial sites 14 – 18 ( Table 1 ). Seven microsatellite loci were included: TA1, Poly-α, PfPK2, TA109, TA2490, C2M34, and C3M69.…”

Section: Methodsmentioning

confidence: 99%

Nonparametric Binary Classification to Distinguish Closely Related versus Unrelated Plasmodium falciparum Parasites

Pluciński

Barratt

2021

The American Journal of Tropical Medicine and Hygiene

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Assessing genetic relatedness of Plasmodium falciparum genotypes is a key component of antimalarial efficacy trials. Previous methods have focused on determining a priori definitions of the level of genetic similarity sufficient to classify two infections as sharing the same strain. However, factors such as mixed-strain infections, allelic suppression, imprecise typing methods, and heterozygosity complicate comparisons of apicomplexan genotypes. Here, we introduce a novel method for nonparametric statistical testing of relatedness for P. falciparum parasites. First, the background distribution of genetic distance between unrelated strains is computed. Second, a threshold genetic distance is computed from this empiric distribution of distances to demarcate genetic distances that are unlikely to have arisen by chance. Third, the genetic distance between paired samples is computed, and paired samples with genetic distances below the threshold are classified as related. The method is designed to work with any arbitrary genetic distance definition. We validated this procedure using two independent approaches to calculating genetic distance. We assessed the concordance of the novel nonparametric classification with a gold-standard Bayesian approach for 175 pairs of recurrent P. falciparum episodes from previously published malaria efficacy trials with microsatellite data from five studies in Guinea and Angola. The novel nonparametric approach was 98% sensitive and 84–89% specific in correctly identifying related genotypes compared with a gold-standard Bayesian algorithm. The approach provides a unified and systematic method to statistically assess relatedness of P. falciparum parasites using arbitrary genetic distance methodologies.

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Continued Low Efficacy of Artemether-Lumefantrine in Angola in 2019

Cited by 46 publications

References 20 publications

Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

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

Nonparametric Binary Classification to Distinguish Closely Related versus Unrelated Plasmodium falciparum Parasites

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