Decreasing efficacy of antimalarial combination therapy in Uganda is explained by decreasing host immunity rather than increasing drug resistance

J Infect Dis. 2009 Mar 1;199(5):758-65. doi: 10.1086/596741.


Background: Improved control efforts are reducing the burden of malaria in Africa but may result in decreased antimalarial immunity.

Methods: A cohort of 129 children aged 1-10 years in Kampala, Uganda, were treated with amodiaquine plus sulfadoxine-pyrimethamine for 396 episodes of uncomplicated malaria over a 29-month period as part of a longitudinal clinical trial.

Results: The risk of treatment failure increased over the course of the study from 5% to 21% (hazard ratio [HR], 2.4 per year [95% confidence interval {CI}, 1.3-4.3]). Parasite genetic polymorphisms were associated with an increased risk of failure, but their prevalence did not change over time. Three markers of antimalarial immunity were associated with a decreased risk of treatment failure: increased age (HR, 0.5 per 5-year increase [95% CI, 0.2-1.2]), living in an area of higher malaria incidence (HR, 0.26 [95% CI, 0.11-0.64]), and recent asymptomatic parasitemia (HR, 0.06 [95% CI, 0.01-0.36]). In multivariate analysis, adjustment for recent asymptomatic parasitemia, but not parasite polymorphisms, removed the association between calendar time and the risk of treatment failure (HR, 1.5 per year [95% CI, 0.7-3.4]), suggesting that worsening treatment efficacy was best explained by decreasing host immunity.

Conclusion: Declining immunity in our study population appeared to be the primary factor underlying decreased efficacy of amodiaquine plus sulfadoxine-pyrimethamine. With improved malaria-control efforts, decreasing immunity may unmask resistance to partially efficacious drugs.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amodiaquine / administration & dosage
  • Amodiaquine / therapeutic use*
  • Animals
  • Antimalarials / therapeutic use*
  • Child
  • Child, Preschool
  • Drug Combinations
  • Drug Resistance*
  • Drug Therapy, Combination
  • Humans
  • Infant
  • Longitudinal Studies
  • Malaria / drug therapy*
  • Malaria / immunology*
  • Plasmodium / drug effects
  • Plasmodium / genetics
  • Pyrimethamine / administration & dosage
  • Pyrimethamine / therapeutic use*
  • Sulfadoxine / administration & dosage
  • Sulfadoxine / therapeutic use*
  • Treatment Failure
  • Uganda


  • Antimalarials
  • Drug Combinations
  • Amodiaquine
  • fanasil, pyrimethamine drug combination
  • Sulfadoxine
  • Pyrimethamine