dhfr and dhps genotype and sulfadoxine-pyrimethamine treatment failure in children with falciparum malaria in the Democratic Republic of Congo.
OBJECTIVE
To determine the relationship between mutations in dhfr and dhps and SP treatment failure in Plasmodium falciparum malaria in the Democratic Republic of the Congo (DRC).


METHODS
Therapeutic efficacy trial was conducted in Rutshuru, Eastern DRC, between June and September 2002, comparing sulfadoxine-pyrimethamine (SP), SP plus amodiaquine (AQSP) and artesunate plus SP (ASSP) regimens for treating malaria in children under 5 years old. We genotyped 212 samples for mutations associated with SP resistance and investigated their association with treatment failure.


RESULTS
In the SP arm, 61% of the subjects experienced treatment failure after 14 days. The failure rate was lower in the combination arms (AQSP: 32%, ASSP: 21%). The dhfr-108 and dhfr-51 mutations were nearly universal while 89% of the samples had at least one additional mutation at dhfr-59, dhps-437 or dhps-540. Dhps mutations had a bigger impact on treatment failure in children with high parasite density: for children with a parasite density <45 000 parasites/microl, the risk of treatment failure was 37% for mutations at dhps-437 and dhps-540 mutation and 21% for neither mutation [risk difference (RD) = 17%, 95% CI: -3%, 36%]. In children with a parasite density >45 000 parasites/microl, the treatment failure risk was 58% and 8% for children with both mutations or neither mutation, respectively (RD = 51%, 95% CI: 34%, 67%).


CONCLUSIONS
Dhps-437 and dhps-540 are strongly associated with SP treatment failure and should be evaluated further as a method for surveillance of SP-based therapy in DRC.
Alker
Alisa P
AP
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA. alkera@med.unc.edu
Kazadi
Walter M
WM
Kutelemeni
Albert K
AK
Bloland
Peter B
PB
Tshefu
Antoinette K
AK
Meshnick
Steven R
SR
D000655:Amodiaquine / Q000627:therapeutic use; D000962:Antimalarials / Q000097:blood / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use; D000077332:Artesunate; D002675:Child, Preschool; D015023:Democratic Republic of the Congo; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D017354:Point Mutation / Q000235:genetics*; D011739:Pyrimethamine / Q000097:blood / Q000627:therapeutic use*; D012423:Rural Health; D013413:Sulfadoxine / Q000097:blood / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D017211:Treatment Failure
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D005819:Genetic Markers; D000655:Amodiaquine; C001205:fanasil, pyrimethamine drug combination; D000077332:Artesunate; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine