A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria

S PICOT, P OLLIARO, M N DE, A BIENVENU, Ric Price, P RINGWALD

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background. An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by Plasmodium falciparum. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number. Methods. Clinical studies of non-severe malaria reporting on target genetic markers (SNPs for pfmdr1, pfcrt, dhfr, dhps, gene copy number for pfmdr1) providing complete information on inclusion criteria, outcome, follow up and genotyping, were included. Three investigators independently extracted data from articles. Results were stratified by gene, codon, drug and duration of follow-up. For each study and aggregate data the random effect odds ratio (OR) with 95%CIs was estimated and presented as Forest plots. An OR with a lower 95 thconfidence interval > 1 was considered consistent with a failure being associated to a given gene mutation. Results. 92 studies were eligible among the selection from computerized search, with information on pfcrt (25/159 studies), pfmdr1 (29/236 studies), dhfr (18/373 studies), dhps (20/195 studies). The risk of therapeutic failure after chloroquine was increased by the presence of pfcrt K76T (Day 28, OR = 7.2 [95%CI: 4.5-11.5]), pfmdr1 N86Y was associated with both chloroquine (Day 28, OR = 1.8 [95%CI: 1.3-2.4]) and amodiaquine failures (OR = 5.4 [95%CI: 2.6-11.3, p < 0.001]). For sulphadoxine- pyrimethamine the dhfr single (S108N) (Day 28, OR = 3.5 [95%CI: 1.9-6.3]) and triple mutants (S108N, N51I, C59R) (Day 28, OR = 3.1 [95%CI: 2.0-4.9]) and dhfr-dhps quintuple mutants (Day 28, OR = 5.2 [95%CI: 3.2-8.8]) also increased the risk of treatment failure. Increased pfmdr1 copy number was correlated with treatment failure following mefloquine (OR = 8.6 [95%CI: 3.3-22.9]). Conclusion. When applying the selection procedure for comparative analysis, few studies fulfilled all inclusion criteria compared to the large number of papers identified, but heterogeneity was limited. Genetic molecular markers were related to an increased risk of therapeutic failure. Guidelines are discussed and a checklist for further studies is proposed.
Original languageEnglish
Pages (from-to)-
JournalMalaria Journal
Volume8
Issue number89
Publication statusPublished - 2009

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Falciparum Malaria
Meta-Analysis
Parasites
Odds Ratio
Treatment Failure
Gene Dosage
Chloroquine
Genetic Markers
Amodiaquine
Mefloquine
Antimalarials
Plasmodium falciparum
Checklist
Drug Resistance
Codon
Genes
Malaria
Single Nucleotide Polymorphism
Research Personnel
Genome

Cite this

@article{ad8670f770cd46d990b35db99ff36077,
title = "A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria",
abstract = "Background. An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by Plasmodium falciparum. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number. Methods. Clinical studies of non-severe malaria reporting on target genetic markers (SNPs for pfmdr1, pfcrt, dhfr, dhps, gene copy number for pfmdr1) providing complete information on inclusion criteria, outcome, follow up and genotyping, were included. Three investigators independently extracted data from articles. Results were stratified by gene, codon, drug and duration of follow-up. For each study and aggregate data the random effect odds ratio (OR) with 95{\%}CIs was estimated and presented as Forest plots. An OR with a lower 95 thconfidence interval > 1 was considered consistent with a failure being associated to a given gene mutation. Results. 92 studies were eligible among the selection from computerized search, with information on pfcrt (25/159 studies), pfmdr1 (29/236 studies), dhfr (18/373 studies), dhps (20/195 studies). The risk of therapeutic failure after chloroquine was increased by the presence of pfcrt K76T (Day 28, OR = 7.2 [95{\%}CI: 4.5-11.5]), pfmdr1 N86Y was associated with both chloroquine (Day 28, OR = 1.8 [95{\%}CI: 1.3-2.4]) and amodiaquine failures (OR = 5.4 [95{\%}CI: 2.6-11.3, p < 0.001]). For sulphadoxine- pyrimethamine the dhfr single (S108N) (Day 28, OR = 3.5 [95{\%}CI: 1.9-6.3]) and triple mutants (S108N, N51I, C59R) (Day 28, OR = 3.1 [95{\%}CI: 2.0-4.9]) and dhfr-dhps quintuple mutants (Day 28, OR = 5.2 [95{\%}CI: 3.2-8.8]) also increased the risk of treatment failure. Increased pfmdr1 copy number was correlated with treatment failure following mefloquine (OR = 8.6 [95{\%}CI: 3.3-22.9]). Conclusion. When applying the selection procedure for comparative analysis, few studies fulfilled all inclusion criteria compared to the large number of papers identified, but heterogeneity was limited. Genetic molecular markers were related to an increased risk of therapeutic failure. Guidelines are discussed and a checklist for further studies is proposed.",
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author = "S PICOT and P OLLIARO and DE, {M N} and A BIENVENU and Ric Price and P RINGWALD",
year = "2009",
language = "English",
volume = "8",
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journal = "Malaria Journal",
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A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. / PICOT, S; OLLIARO, P; DE, M N; BIENVENU, A; Price, Ric; RINGWALD, P.

In: Malaria Journal, Vol. 8, No. 89, 2009, p. -.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria

AU - PICOT, S

AU - OLLIARO, P

AU - DE, M N

AU - BIENVENU, A

AU - Price, Ric

AU - RINGWALD, P

PY - 2009

Y1 - 2009

N2 - Background. An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by Plasmodium falciparum. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number. Methods. Clinical studies of non-severe malaria reporting on target genetic markers (SNPs for pfmdr1, pfcrt, dhfr, dhps, gene copy number for pfmdr1) providing complete information on inclusion criteria, outcome, follow up and genotyping, were included. Three investigators independently extracted data from articles. Results were stratified by gene, codon, drug and duration of follow-up. For each study and aggregate data the random effect odds ratio (OR) with 95%CIs was estimated and presented as Forest plots. An OR with a lower 95 thconfidence interval > 1 was considered consistent with a failure being associated to a given gene mutation. Results. 92 studies were eligible among the selection from computerized search, with information on pfcrt (25/159 studies), pfmdr1 (29/236 studies), dhfr (18/373 studies), dhps (20/195 studies). The risk of therapeutic failure after chloroquine was increased by the presence of pfcrt K76T (Day 28, OR = 7.2 [95%CI: 4.5-11.5]), pfmdr1 N86Y was associated with both chloroquine (Day 28, OR = 1.8 [95%CI: 1.3-2.4]) and amodiaquine failures (OR = 5.4 [95%CI: 2.6-11.3, p < 0.001]). For sulphadoxine- pyrimethamine the dhfr single (S108N) (Day 28, OR = 3.5 [95%CI: 1.9-6.3]) and triple mutants (S108N, N51I, C59R) (Day 28, OR = 3.1 [95%CI: 2.0-4.9]) and dhfr-dhps quintuple mutants (Day 28, OR = 5.2 [95%CI: 3.2-8.8]) also increased the risk of treatment failure. Increased pfmdr1 copy number was correlated with treatment failure following mefloquine (OR = 8.6 [95%CI: 3.3-22.9]). Conclusion. When applying the selection procedure for comparative analysis, few studies fulfilled all inclusion criteria compared to the large number of papers identified, but heterogeneity was limited. Genetic molecular markers were related to an increased risk of therapeutic failure. Guidelines are discussed and a checklist for further studies is proposed.

AB - Background. An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by Plasmodium falciparum. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number. Methods. Clinical studies of non-severe malaria reporting on target genetic markers (SNPs for pfmdr1, pfcrt, dhfr, dhps, gene copy number for pfmdr1) providing complete information on inclusion criteria, outcome, follow up and genotyping, were included. Three investigators independently extracted data from articles. Results were stratified by gene, codon, drug and duration of follow-up. For each study and aggregate data the random effect odds ratio (OR) with 95%CIs was estimated and presented as Forest plots. An OR with a lower 95 thconfidence interval > 1 was considered consistent with a failure being associated to a given gene mutation. Results. 92 studies were eligible among the selection from computerized search, with information on pfcrt (25/159 studies), pfmdr1 (29/236 studies), dhfr (18/373 studies), dhps (20/195 studies). The risk of therapeutic failure after chloroquine was increased by the presence of pfcrt K76T (Day 28, OR = 7.2 [95%CI: 4.5-11.5]), pfmdr1 N86Y was associated with both chloroquine (Day 28, OR = 1.8 [95%CI: 1.3-2.4]) and amodiaquine failures (OR = 5.4 [95%CI: 2.6-11.3, p < 0.001]). For sulphadoxine- pyrimethamine the dhfr single (S108N) (Day 28, OR = 3.5 [95%CI: 1.9-6.3]) and triple mutants (S108N, N51I, C59R) (Day 28, OR = 3.1 [95%CI: 2.0-4.9]) and dhfr-dhps quintuple mutants (Day 28, OR = 5.2 [95%CI: 3.2-8.8]) also increased the risk of treatment failure. Increased pfmdr1 copy number was correlated with treatment failure following mefloquine (OR = 8.6 [95%CI: 3.3-22.9]). Conclusion. When applying the selection procedure for comparative analysis, few studies fulfilled all inclusion criteria compared to the large number of papers identified, but heterogeneity was limited. Genetic molecular markers were related to an increased risk of therapeutic failure. Guidelines are discussed and a checklist for further studies is proposed.

KW - amodiaquine

KW - artesunate

KW - chloroquine

KW - fansidar

KW - mefloquine

KW - molecular marker

KW - antimalarial agent

KW - article

KW - clinical trial

KW - codon

KW - comparative study

KW - correlation analysis

KW - disease resistance

KW - follow up

KW - gene

KW - gene mutation

KW - gene number

KW - gene targeting

KW - genetic marker

KW - genome

KW - genotype

KW - human

KW - malaria falciparum

KW - meta analysis

KW - mutant

KW - outcome assessment

KW - Plasmodium falciparum

KW - risk factor

KW - single nucleotide polymorphism

KW - systematic review

KW - treatment duration

KW - treatment failure

KW - treatment outcome

KW - treatment response

KW - animal

KW - drug effect

KW - drug resistance

KW - gene dosage

KW - genetic polymorphism

KW - genetics

KW - review

KW - Animals

KW - Antimalarials

KW - Drug Resistance

KW - Gene Dosage

KW - Genes, Protozoan

KW - Genetic Markers

KW - Humans

KW - Malaria, Falciparum

KW - Polymorphism, Genetic

KW - Treatment Failure

M3 - Article

VL - 8

SP - -

JO - Malaria Journal

JF - Malaria Journal

SN - 1475-2875

IS - 89

ER -