Effect of trimethoprim-sulphamethoxazole on the risk of malaria in HIV-infected Ugandan children living in an area of widespread antifolate resistance.
BACKGROUND
Daily trimethoprim-sulfamethoxazole (TS) protects against malaria, but efficacy may be diminished as anti-folate resistance increases. This study assessed the incidence of falciparum malaria and the prevalence of resistance-conferring Plasmodium falciparum mutations in HIV-infected children receiving daily TS and HIV-uninfected children not taking TS.


METHODS
Subjects were 292 HIV-infected and 517 uninfected children from two cohort studies in Kampala, Uganda observed from August 2006 to December 2008. Daily TS was given to HIV-infected, but not HIV-uninfected children and all participants were provided an insecticide-treated bed net. Standardized protocols were used to measure the incidence of malaria and identify markers of antifolate resistance.


RESULTS
Sixty-five episodes of falciparum malaria occurred in HIV-infected and 491 episodes in uninfected children during the observation period. TS was associated with a protective efficacy of 80% (0.10 vs. 0.45 episodes per person year, p < 0.001), and efficacy did not vary over three consecutive 9.5 month periods (81%, 74%, 80% respectively, p = 0.506). The prevalences of dhfr 51I, 108N, and 59R and dhps 437G and 540E mutations were each over 90% among parasites infecting both HIV-infected and uninfected children. Prevalence of the dhfr 164L mutation, which is associated with high-level resistance, was significantly higher in parasites from HIV-infected compared to uninfected children (8% vs. 1%, p = 0.001). Sequencing of the dhfr and dhps genes identified only one additional polymorphism, dhps 581G, in 2 of 30 samples from HIV-infected and 0 of 54 samples from uninfected children.


CONCLUSIONS
Despite high prevalence of known anti-folate resistance-mediating mutations, TS prophylaxis was highly effective against malaria, but was associated with presence of dhfr 164L mutation.
Gasasira
Anne F
AF
School of Medicine, Makerere University Kampala, Uganda. agasasira@gmail.com
Kamya
Moses R
MR
Ochong
Edwin O
EO
Vora
Neil
N
Achan
Jane
J
Charlebois
Edwin
E
Ruel
Theodore
T
Kateera
Fredrick
F
Meya
Denise N
DN
Havlir
Diane
D
Rosenthal
Philip J
PJ
Dorsey
Grant
G
D000962:Antimalarials / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004094:Dihydropteroate Synthase / Q000235:genetics* / Q000378:metabolism; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005500:Follow-Up Studies; D015658:HIV Infections / Q000150:complications / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007223:Infant; D057148:Insecticide-Treated Bednets; D016778:Malaria, Falciparum / Q000150:complications / Q000453:epidemiology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015995:Prevalence; D012307:Risk Factors; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*; D014454:Uganda / Q000453:epidemiology
D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase