dhfr and dhps genotype and sulfadoxine-pyrimethamine treatment failure in children with falciparum malaria in the Democratic Republic of Congo

• Published in: Tropical medicine & international health Vol. 13; no. 11; pp. 1384 - 1391
• Main Authors: Alker, Alisa P, Kazadi, Walter M, Kutelemeni, Albert K, Bloland, Peter B, Tshefu, Antoinette K, Meshnick, Steven R
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.11.2008; Blackwell Publishing Ltd; Blackwell Science
• Subjects: Amodiaquine; Amodiaquine - therapeutic use; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials; Antimalarials - blood; Antimalarials - therapeutic use; Artemisinins; Artemisinins - therapeutic use; Artesunate; Biological and medical sciences; blood; Child, Preschool; Congo (Democratic Republic); Democratic Republic of the Congo; dihidrofolato reductasa; dihidropteroato sintasa; dihydrofolate reductase; dihydrofolate réductase; Dihydropteroate Synthase; Dihydropteroate Synthase - genetics; Drug Combinations; drug resistance; Drug Resistance - genetics; Drug therapy; Drug Therapy, Combination; Female; General aspects; Genetic Markers; genetics; Genotype; Genotype & phenotype; Human protozoal diseases; Humans; Infant; Infectious diseases; Malaria; Malaria, Falciparum; Malaria, Falciparum - drug therapy; Malaria, Falciparum - genetics; Male; Medical sciences; Mene; Mutation; Parasites; Parasitic diseases; Pediatrics; Pharmacology. Drug treatments; Plasmodium falciparum; Point Mutation; Point Mutation - genetics; Protozoal diseases; Pyrimethamine; Pyrimethamine - blood; Pyrimethamine - therapeutic use; resistencia a fármacos; Rural Health; résistance aux médicaments; Sulfadoxine; Sulfadoxine - blood; Sulfadoxine - therapeutic use; Tetrahydrofolate Dehydrogenase; Tetrahydrofolate Dehydrogenase - genetics; therapeutic use; Treatment Failure; Vector-borne diseases; Congo; Africa; Congo-Democratic Republic of Congo; Congo (Democratic Republic); Antimalarial; Protozoal disease; Plasmodium falciparum; Microbiological investigation; Dihydropteroate synthase; Tropical medicine; Antiinfectious; Sulfadoxine; Dihydrofolate reductase; Child; Failure; Human; Protozoa; Apicomplexa; Treatment resistance; Typing; Malaria; Enzyme; Transferases; Pyrimethamine; Genotype; Parasitosis; Infection; Treatment; Parasiticide; Oxidoreductases; drug resistance; Antibacterial agent
• ISSN: 1360-2276; 1365-3156; 1365-3156
• DOI: 10.1111/j.1365-3156.2008.02150.x

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). 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. 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/μl, 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/μl, the treatment failure risk was 58% and 8% for children with both mutations or neither mutation, respectively (RD = 51%, 95% CI: 34%, 67%). 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.