Monitoring for multidrug-resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola.
OBJECTIVE
To assess the extent of drug resistance in Uige through molecular genetic analysis and to test whether the dhfr triple mutant alleles present in Angola are of southeast Asian origin.


METHODS
Seventy-one samples of blood from children admitted to the Pediatric Emergency Unit of Uige Provincial Hospital in 2004 were screened for resistance mutations at pfcrt, pfmdr1, pfdhfr, pfdhps and pfATPase6.


RESULTS
Mutations in pfcrt (codon76), pfmdr1 (codon86), pfdhfr (codons 51, 59, 108) and pfdhps (codons 436, 437) were common. Among the 66 isolates for which we were able to determine complete genetic information 13.7% carried all seven of these mutations. Flanking microsatellite analysis revealed the triple mutant pfdhfr was derived from the southeast Asian lineage, while the N51I+S108N double mutant pfdhfr alleles are a local origin. pfATPase6 mutations were rare and S769N was not found.


CONCLUSIONS
The parasite population of Uige Angola has high frequency mutations in pfcrt, dhfr and dhps associated with resistance to chloroquine and sulphadoxine pyrimethamine, reflecting past reliance on these two drugs which were the mainstay of treatment until recently. Our findings show that drug resistance in Uige has occurred through a combination of local drug pressure and the regional and international dispersal of resistance mutant alleles.
Menegon
Michela
M
Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy.
Pearce
Richard J
RJ
Inojosa
Walter O
WO
Pisani
Vincenzo
V
Abel
Paulo M
PM
Matondo
Alexandre
A
Bisoffi
Zeno
Z
Majori
Giancarlo
G
Ord
Rosalynn
R
Warhurst
David C
DC
Roper
Cally
C
Severini
Carlo
C
D000810:Angola; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000627:therapeutic use*
D000962:Antimalarials; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011739:Pyrimethamine; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum