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Decreased In Vitro Artemisinin Sensitivity of Plasmodium falciparum across India.

ABSTRACT: Artemisinin-based combination therapy (ACT) has been used to treat uncomplicated Plasmodium falciparum infections in India since 2004. Since 2008, a decrease in artemisinin effectiveness has been seen throughout the Greater Mekong Subregion. The geographic proximity and ecological similarities of northeastern India to Southeast Asia may differentially affect the long-term management and sustainability of ACT in India. In order to collect baseline data on variations in ACT sensitivity in Indian parasites, 12 P. falciparum isolates from northeast India and 10 isolates from southwest India were studied in vitro Ring-stage survival assay (RSA) showed reduced sensitivity to dihydroartemisinin in 50% of the samples collected in northeast India in 2014 and 2015. Two of the 10 assayed samples from the southwest region of India from as far back as 2012 also showed decreased sensitivity to artemisinin. In both these regions, kelch gene sequences were not predictive of reduced artemisinin sensitivity, as measured by RSA. The present data justify future investments in integrated approaches involving clinical follow-up studies, in vitro survival assays, and molecular markers for tracking potential changes in the effectiveness of artemisinin against P. falciparum throughout India.

SUBMITTER: Chakrabarti R

PROVIDER: S-EPMC6761557 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Decreased In Vitro Artemisinin Sensitivity of Plasmodium falciparum across India.

Chakrabarti Rimi R White John J Babar Prasad H PH Kumar Shiva S Mudeppa Devaraja Gouda DG Mascarenhas Anjali A Pereira Ligia L Dash Rashmi R Maki Jennifer N JN Sharma Ambika A Gogoi Kabita K Sarma Devojit K DK Pal Bhowmick Ipsita I Manoharan Suresh Kumar SK Gomes Edwin E Mahanta Jagadish J Mohapatra Pradyumna Kishore PK Chery Laura L Rathod Pradipsinh K PK

Antimicrobial agents and chemotherapy 20190923 10

Artemisinin-based combination therapy (ACT) has been used to treat uncomplicated Plasmodium falciparum infections in India since 2004. Since 2008, a decrease in artemisinin effectiveness has been seen throughout the Greater Mekong Subregion. The geographic proximity and ecological similarities of northeastern India to Southeast Asia may differentially affect the long-term management and sustainability of ACT in India. In order to collect baseline data on variations in ACT sensitivity in I ...[more]

PMID: 31332065

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Project description:BackgroundAnti-malarial drugs are the major focus in the prevention and treatment of malaria. Artemisinin-based combination therapy (ACT) is the WHO recommended first-line treatment for Plasmodium falciparum malaria across the endemic world. Also ACT is increasingly relied upon in treating Plasmodium vivax malaria where chloroquine is failing. The emergence of artemisinin drug-resistant parasites is a serious threat faced by global malaria control programmes. Therefore, the success of treatment and intervention strategies is highly pegged on understanding the genetic basis of resistance.MethodsHere, resistance in P. falciparum was generated in vitro for artemisinin to produce levels above clinically relevant concentrations in vivo, and the molecular haplotypes investigated. Genomic DNA was extracted using the QIAamp mini DNA kit. DNA sequences of Pfk13, Pfcrt and Pfmdr1 genes were amplified by PCR and the amplicons were successfully sequenced. Single nucleotide polymorphisms were traced by standard bidirectional sequencing and reading the transcripts against wild-type sequences in Codon code Aligner Version 5.1 and NCBI blast.ResultsExposure of parasite strains D6 and W2 to artemisinin resulted in a decrease in parasite susceptibility to artemisinin (W2 and D6) and lumefantrine (D6 only). The parasites exhibited elevated IC50s to multiple artemisinins, with >twofold resistance to artemisinin; however, the resistance index obtained with standard methods was noticeably less than expected for parasite lines recovered from 50 µg/ml 48 h drug pressure. The change in parasite susceptibility was associated with Pfmdr-185K mutation, a mutation never reported before. The Pfcrt-CVMNK genotype (Pfcrt codons 72-76) was retained and notably, the study did not detect any polymorphisms reported to reduce P. falciparum susceptibility in vivo in the coding sequences of the Pfk13 gene.DiscussionThis data demonstrate that P. falciparum has the capacity to develop resistance to artemisinin derivatives in vitro and that this phenotype is achieved by mutations in Pfmdr1, the genetic changes that are also underpinning lumefantrine resistance. This finding is of practical importance, because artemisinin drugs in Kenya are used in combination with lumefantrine for the treatment of malaria.ConclusionArtemisinin resistance phenotype as has been shown in this work, is a decrease in parasites susceptibility to artemisinin derivatives together with the parasite's ability to recover from drug-induced dormancy after exposure to drug dosage above the in vivo clinical concentrations. The study surmises that Pfmdr1 may play a role in the anti-malarial activity of artemisinin.

Project description:BackgroundArtemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.MethodsIn two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.ResultsWe studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.ConclusionsP. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)

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Decreased In Vitro Artemisinin Sensitivity of Plasmodium falciparum across India.

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Decreased <i>In Vitro</i> Artemisinin Sensitivity of <i>Plasmodium falciparum</i> across India.

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