Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India

Sneh Shalini, Saumyadripta Chaudhuri, Patrick L. Sutton, Neelima Mishra, Nalini Srivastava, Joseph K. David, K. John Ravindran, Jane M. Carlton, Alex Eapen

Research output: Contribution to journalArticle

Abstract

Background: Assessing the Plasmodium vivax burden in India is complicated by the potential threat of an emerging chloroquine (CQ) resistant parasite population from neighbouring countries in Southeast Asia. Chennai, the capital of Tamil Nadu and an urban setting for P. vivax in southern India, was selected as a sentinel site for investigating CQ efficacy and sensitivity in vivax malaria. Methods. CQ efficacy was evaluated with a 28-day in vivo therapeutic study, while CQ sensitivity was measured with an in vitro drug susceptibility assay. In both studies, isolates also underwent molecular genotyping to investigate correlations between parasite diversity and drug susceptibility to CQ. Molecular genotyping included sequencing a 604 base pair (bp) fragment of the P. vivax multidrug resistant gene-1 (Pvmdr1) for single nucleotide polymorphisms (SNPs) and also the amplification of eight microsatellite (MS) loci located across the genome on eight different chromosomes. Results: In the 28-day in vivo study (N=125), all subjects were aparasitaemic by Day 14. Passive case surveillance continuing beyond Day 28 in 22 subjects exposed 17 recurrent infections, which ranged from 44 to 148 days post-enrollment. Pvmdr1 sequencing of these recurrent infections revealed that 93.3% had identical mutant haplotypes (958M/Y976/1076L) to their baseline Day 0 infection. MS genotyping further revealed that nine infection pairs were related with ≥75% haplotype similarity (same allele at six or more loci). To test the impact of this mutation on CQ efficacy, an in vitro drug assay (N=68) was performed. No correlation between IC50 values and the percentage of ring-stage parasites prior to culture was observed (rsadj: -0.00063, p = 0.3307) and the distribution of alleles among the Pvmdr1 SNPs and MS haplotypes showed no significant associations with IC50 values. Conclusions: Plasmodium vivax was found to be susceptible to CQ drug treatment in both the in vivo therapeutic drug study and the in vitro drug assay. Though the mutant 1076L of Pvmdr1 was found in a majority of isolates tested, this single mutation did not associate with CQ resistance. MS haplotypes revealed strong heterogeneity in this population, indicating a low probability of reinfection with highly related haplotypes.

Original languageEnglish (US)
Article number129
JournalMalaria Journal
Volume13
Issue number1
DOIs
StatePublished - Mar 31 2014

Fingerprint

Plasmodium vivax
Chloroquine
India
Haplotypes
Pharmaceutical Preparations
Microsatellite Repeats
Parasites
Infection
Genes
Inhibitory Concentration 50
Single Nucleotide Polymorphism
Alleles
Vivax Malaria
Southeastern Asia
Mutation
Population Characteristics
Base Pairing
Chromosomes
Genome
Therapeutics

Keywords

  • Chennai
  • Chloroquine
  • Genetic diversity
  • In vitro
  • In vivo
  • Plasmodium vivax

ASJC Scopus subject areas

  • Infectious Diseases
  • Parasitology

Cite this

Shalini, S., Chaudhuri, S., Sutton, P. L., Mishra, N., Srivastava, N., David, J. K., ... Eapen, A. (2014). Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India. Malaria Journal, 13(1), [129]. https://doi.org/10.1186/1475-2875-13-129

Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India. / Shalini, Sneh; Chaudhuri, Saumyadripta; Sutton, Patrick L.; Mishra, Neelima; Srivastava, Nalini; David, Joseph K.; Ravindran, K. John; Carlton, Jane M.; Eapen, Alex.

In: Malaria Journal, Vol. 13, No. 1, 129, 31.03.2014.

Research output: Contribution to journalArticle

Shalini, S, Chaudhuri, S, Sutton, PL, Mishra, N, Srivastava, N, David, JK, Ravindran, KJ, Carlton, JM & Eapen, A 2014, 'Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India', Malaria Journal, vol. 13, no. 1, 129. https://doi.org/10.1186/1475-2875-13-129
Shalini S, Chaudhuri S, Sutton PL, Mishra N, Srivastava N, David JK et al. Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India. Malaria Journal. 2014 Mar 31;13(1). 129. https://doi.org/10.1186/1475-2875-13-129
Shalini, Sneh ; Chaudhuri, Saumyadripta ; Sutton, Patrick L. ; Mishra, Neelima ; Srivastava, Nalini ; David, Joseph K. ; Ravindran, K. John ; Carlton, Jane M. ; Eapen, Alex. / Chloroquine efficacy studies confirm drug susceptibility of Plasmodium vivax in Chennai, India. In: Malaria Journal. 2014 ; Vol. 13, No. 1.
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abstract = "Background: Assessing the Plasmodium vivax burden in India is complicated by the potential threat of an emerging chloroquine (CQ) resistant parasite population from neighbouring countries in Southeast Asia. Chennai, the capital of Tamil Nadu and an urban setting for P. vivax in southern India, was selected as a sentinel site for investigating CQ efficacy and sensitivity in vivax malaria. Methods. CQ efficacy was evaluated with a 28-day in vivo therapeutic study, while CQ sensitivity was measured with an in vitro drug susceptibility assay. In both studies, isolates also underwent molecular genotyping to investigate correlations between parasite diversity and drug susceptibility to CQ. Molecular genotyping included sequencing a 604 base pair (bp) fragment of the P. vivax multidrug resistant gene-1 (Pvmdr1) for single nucleotide polymorphisms (SNPs) and also the amplification of eight microsatellite (MS) loci located across the genome on eight different chromosomes. Results: In the 28-day in vivo study (N=125), all subjects were aparasitaemic by Day 14. Passive case surveillance continuing beyond Day 28 in 22 subjects exposed 17 recurrent infections, which ranged from 44 to 148 days post-enrollment. Pvmdr1 sequencing of these recurrent infections revealed that 93.3{\%} had identical mutant haplotypes (958M/Y976/1076L) to their baseline Day 0 infection. MS genotyping further revealed that nine infection pairs were related with ≥75{\%} haplotype similarity (same allele at six or more loci). To test the impact of this mutation on CQ efficacy, an in vitro drug assay (N=68) was performed. No correlation between IC50 values and the percentage of ring-stage parasites prior to culture was observed (rsadj: -0.00063, p = 0.3307) and the distribution of alleles among the Pvmdr1 SNPs and MS haplotypes showed no significant associations with IC50 values. Conclusions: Plasmodium vivax was found to be susceptible to CQ drug treatment in both the in vivo therapeutic drug study and the in vitro drug assay. Though the mutant 1076L of Pvmdr1 was found in a majority of isolates tested, this single mutation did not associate with CQ resistance. MS haplotypes revealed strong heterogeneity in this population, indicating a low probability of reinfection with highly related haplotypes.",
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AU - Chaudhuri, Saumyadripta

AU - Sutton, Patrick L.

AU - Mishra, Neelima

AU - Srivastava, Nalini

AU - David, Joseph K.

AU - Ravindran, K. John

AU - Carlton, Jane M.

AU - Eapen, Alex

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N2 - Background: Assessing the Plasmodium vivax burden in India is complicated by the potential threat of an emerging chloroquine (CQ) resistant parasite population from neighbouring countries in Southeast Asia. Chennai, the capital of Tamil Nadu and an urban setting for P. vivax in southern India, was selected as a sentinel site for investigating CQ efficacy and sensitivity in vivax malaria. Methods. CQ efficacy was evaluated with a 28-day in vivo therapeutic study, while CQ sensitivity was measured with an in vitro drug susceptibility assay. In both studies, isolates also underwent molecular genotyping to investigate correlations between parasite diversity and drug susceptibility to CQ. Molecular genotyping included sequencing a 604 base pair (bp) fragment of the P. vivax multidrug resistant gene-1 (Pvmdr1) for single nucleotide polymorphisms (SNPs) and also the amplification of eight microsatellite (MS) loci located across the genome on eight different chromosomes. Results: In the 28-day in vivo study (N=125), all subjects were aparasitaemic by Day 14. Passive case surveillance continuing beyond Day 28 in 22 subjects exposed 17 recurrent infections, which ranged from 44 to 148 days post-enrollment. Pvmdr1 sequencing of these recurrent infections revealed that 93.3% had identical mutant haplotypes (958M/Y976/1076L) to their baseline Day 0 infection. MS genotyping further revealed that nine infection pairs were related with ≥75% haplotype similarity (same allele at six or more loci). To test the impact of this mutation on CQ efficacy, an in vitro drug assay (N=68) was performed. No correlation between IC50 values and the percentage of ring-stage parasites prior to culture was observed (rsadj: -0.00063, p = 0.3307) and the distribution of alleles among the Pvmdr1 SNPs and MS haplotypes showed no significant associations with IC50 values. Conclusions: Plasmodium vivax was found to be susceptible to CQ drug treatment in both the in vivo therapeutic drug study and the in vitro drug assay. Though the mutant 1076L of Pvmdr1 was found in a majority of isolates tested, this single mutation did not associate with CQ resistance. MS haplotypes revealed strong heterogeneity in this population, indicating a low probability of reinfection with highly related haplotypes.

AB - Background: Assessing the Plasmodium vivax burden in India is complicated by the potential threat of an emerging chloroquine (CQ) resistant parasite population from neighbouring countries in Southeast Asia. Chennai, the capital of Tamil Nadu and an urban setting for P. vivax in southern India, was selected as a sentinel site for investigating CQ efficacy and sensitivity in vivax malaria. Methods. CQ efficacy was evaluated with a 28-day in vivo therapeutic study, while CQ sensitivity was measured with an in vitro drug susceptibility assay. In both studies, isolates also underwent molecular genotyping to investigate correlations between parasite diversity and drug susceptibility to CQ. Molecular genotyping included sequencing a 604 base pair (bp) fragment of the P. vivax multidrug resistant gene-1 (Pvmdr1) for single nucleotide polymorphisms (SNPs) and also the amplification of eight microsatellite (MS) loci located across the genome on eight different chromosomes. Results: In the 28-day in vivo study (N=125), all subjects were aparasitaemic by Day 14. Passive case surveillance continuing beyond Day 28 in 22 subjects exposed 17 recurrent infections, which ranged from 44 to 148 days post-enrollment. Pvmdr1 sequencing of these recurrent infections revealed that 93.3% had identical mutant haplotypes (958M/Y976/1076L) to their baseline Day 0 infection. MS genotyping further revealed that nine infection pairs were related with ≥75% haplotype similarity (same allele at six or more loci). To test the impact of this mutation on CQ efficacy, an in vitro drug assay (N=68) was performed. No correlation between IC50 values and the percentage of ring-stage parasites prior to culture was observed (rsadj: -0.00063, p = 0.3307) and the distribution of alleles among the Pvmdr1 SNPs and MS haplotypes showed no significant associations with IC50 values. Conclusions: Plasmodium vivax was found to be susceptible to CQ drug treatment in both the in vivo therapeutic drug study and the in vitro drug assay. Though the mutant 1076L of Pvmdr1 was found in a majority of isolates tested, this single mutation did not associate with CQ resistance. MS haplotypes revealed strong heterogeneity in this population, indicating a low probability of reinfection with highly related haplotypes.

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KW - Chloroquine

KW - Genetic diversity

KW - In vitro

KW - In vivo

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