Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1.
BACKGROUND
Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce.


METHODS
We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response.


RESULTS
The treatment failure (TF) rate reached 13%. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60%, 67%, 20%, 40%, and 39% of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P= .01). The combined presence of the quadruple mutant pvdhfr 57L+58R+61M+117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P= .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites.


CONCLUSIONS
The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ+SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ+SP in countries where these drugs are used.
Marfurt
Jutta
J
Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland.
de Monbrison
Frédérique
F
Brega
Sara
S
Barbollat
Laetitia
L
Müller
Ivo
I
Sie
Albert
A
Goroti
Mary
M
Reeder
John C
JC
Beck
Hans-Peter
HP
Picot
Stéphane
S
Genton
Blaise
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000655:Amodiaquine / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D016780:Malaria, Vivax / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D020125:Mutation, Missense; D010219:Papua New Guinea; D010966:Plasmodium vivax / Q000187:drug effects* / Q000235:genetics; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics*; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D004338:Drug Combinations; D005819:Genetic Markers; D015800:Protozoan Proteins; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine