Intrahost selection of Plasmodium falciparum pfmdr1 alleles after antimalarial treatment on the northwestern border of Thailand.
BACKGROUND
Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure.


METHODS
In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment.


RESULTS
Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P<.001).


CONCLUSIONS
Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites.
Uhlemann
Anne-Catrin
AC
Centre for Infection, Division of Cellular and Molecular Medicine, St. George's, University of London, London, United Kingdom.
McGready
Rose
R
Ashley
Elizabeth A
EA
Brockman
Alan
A
Singhasivanon
Pratap
P
Krishna
Sanjeev
S
White
Nicholas J
NJ
Nosten
Francois
F
Price
Ric N
RN
D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000032:analysis / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D013785:Thailand
D000962:Antimalarials; D016054:DNA, Protozoan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum