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

Abstract

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.

• Authors: Bryan Greenhouse, Madeline Slater, Denise Njama-Meya, Bridget Nzarubara, Catherine Maiteki-Sebuguzi, Tamara D Clark, Sarah G Staedke, Moses R Kamya, Alan Hubbard, Philip J Rosenthal, Grant Dorsey
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 199 Issue 5 Pg. 758-65 (Mar 01 2009) ISSN: 0022-1899 [Print] United States
• PMID: 19199542 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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