PMID- 19238219
OWN - NLM
STAT- MEDLINE
DCOM- 20090413
LR  - 20220408
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 4
IP  - 2
DP  - 2009
TI  - High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in 
      northern Tanzania and the emergence of dhps resistance mutation at Codon 581.
PG  - e4569
LID - 10.1371/journal.pone.0004569 [doi]
LID - e4569
AB  - BACKGROUND: Sulphadoxine-pyrimethamine (SP) a widely used treatment for 
      uncomplicated malaria and recommended for intermittent preventive treatment of 
      malaria in pregnancy, is being investigated for intermittent preventive treatment 
      of malaria in infants (IPTi). High levels of drug resistance to SP have been 
      reported from north-eastern Tanzania associated with mutations in parasite genes. 
      This study compared the in vivo efficacy of SP in symptomatic 6-59 month children 
      with uncomplicated malaria and in asymptomatic 2-10 month old infants. 
      METHODOLOGY AND PRINCIPAL FINDINGS: An open label single arm (SP) standard 28 day 
      in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old 
      symptomatic children and a modified protocol used in 2 to 10 months old 
      asymptomatic infants. Enrolment was stopped early (87 in the symptomatic and 25 
      in the asymptomatic studies) due to the high failure rate. Molecular markers were 
      examined for recrudescence, re-infection and markers of drug resistance and a 
      review of literature of studies looking for the 581G dhps mutation was carried 
      out. In symptomatic children PCR-corrected early treatment failure was 38.8% (95% 
      CI 26.8-50.8) and total failures by day 28 were 82.2% (95% CI 72.5-92.0). There 
      was no significant difference in treatment failures between asymptomatic and 
      symptomatic children. 96% of samples carried parasites with mutations at codons 
      51, 59 and 108 in the dhfr gene and 63% carried a double mutation at codons 437 
      and 540. 55% carried a third mutation with the addition of a mutation at codon 
      581 in the dhps gene. This triple: triple haplotype maybe associated with earlier 
      treatment failure. CONCLUSION: In northern Tanzania SP is a failed drug for 
      treatment and its utility for prophylaxis is doubtful. The study found a new 
      combination of parasite mutations that maybe associated with increased and 
      earlier failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT00361114.
FAU - Gesase, Samwel
AU  - Gesase S
AD  - National Institute for Medical Research, Tanga Centre, Tanga, Tanzania.
FAU - Gosling, Roly D
AU  - Gosling RD
FAU - Hashim, Ramadhan
AU  - Hashim R
FAU - Ord, Rosalynn
AU  - Ord R
FAU - Naidoo, Inbarani
AU  - Naidoo I
FAU - Madebe, Rashid
AU  - Madebe R
FAU - Mosha, Jacklin F
AU  - Mosha JF
FAU - Joho, Angel
AU  - Joho A
FAU - Mandia, Victor
AU  - Mandia V
FAU - Mrema, Hedwiga
AU  - Mrema H
FAU - Mapunda, Ephraim
AU  - Mapunda E
FAU - Savael, Zacharia
AU  - Savael Z
FAU - Lemnge, Martha
AU  - Lemnge M
FAU - Mosha, Frank W
AU  - Mosha FW
FAU - Greenwood, Brian
AU  - Greenwood B
FAU - Roper, Cally
AU  - Roper C
FAU - Chandramohan, Daniel
AU  - Chandramohan D
LA  - eng
SI  - ClinicalTrials.gov/NCT00361114
PT  - Controlled Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090224
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Codon)
RN  - 0 (Drug Combinations)
RN  - 37338-39-9 (fanasil, pyrimethamine drug combination)
RN  - 88463U4SM5 (Sulfadoxine)
RN  - Z3614QOX8W (Pyrimethamine)
SB  - IM
MH  - Animals
MH  - Child, Preschool
MH  - Codon
MH  - Drug Combinations
MH  - Drug Resistance/*genetics
MH  - Female
MH  - Genes, Protozoan/*genetics
MH  - Humans
MH  - Infant
MH  - Male
MH  - Mutation
MH  - Plasmodium falciparum/drug effects/*genetics
MH  - Polymerase Chain Reaction
MH  - Pyrimethamine/*administration & dosage/pharmacology
MH  - Sulfadoxine/*administration & dosage/pharmacology
MH  - Tanzania
MH  - Treatment Failure
PMC - PMC2644264
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2009/02/25 09:00
MHDA- 2009/04/14 09:00
PMCR- 2009/02/24
CRDT- 2009/02/25 09:00
PHST- 2008/08/01 00:00 [received]
PHST- 2008/12/12 00:00 [accepted]
PHST- 2009/02/25 09:00 [entrez]
PHST- 2009/02/25 09:00 [pubmed]
PHST- 2009/04/14 09:00 [medline]
PHST- 2009/02/24 00:00 [pmc-release]
AID - 08-PONE-RA-05773R1 [pii]
AID - 10.1371/journal.pone.0004569 [doi]
PST - ppublish
SO  - PLoS One. 2009;4(2):e4569. doi: 10.1371/journal.pone.0004569. Epub 2009 Feb 24.