Assessing the Efficacy of Sulfadoxine-Pyrimethamine,Sulfadoxine-Pyrimethamine + Artesunate, and Artemether-Lumefantrinefor treatment of uncomplicated malaria in Tanzanian Children Open Access

Abstract

In 2001 the Tanzanian government adopted sulfadoxine-pyrimethamine (SP) as the first-line antimalarial treatment. Continuous monitoring of antimalarial efficacy is crucial in light of increasing parasite resistance to antimalarials. We measured in vivo efficacy of SP alone versus SP-artesunate (SPAS) or artemether-lumefantrine (AL), three and five years after SP introduction and prior to widespread deployment of AL. Patients <5 years old with uncomplicated P. falciparum monoinfection were enrolled and randomized to receive either SP, SPAS, or AL using the standard WHO 28-day protocol. PCR genotyping was used to distinguish recrudescence from re-infection and characterize known molecular markers of antimalarial drug resistance. In 2004 we enrolled 425 patients; 143 each in the SP and SPAS arms and 139 in the AL arm, while in 2006 we enrolled 361 patients: 121 in the SP arm, 122 in the SPAS arm, and 118 in the AL arm. The 2006 uncorrected cure rates were 39%, 56%, and 77% in the SP, SPAS, and AL groups, respectively. This represents a significant decrease in efficacy for SP and SPAS since 2004, when respective uncorrected cure rates were 58%, 78%, and 80%, respectively. The PCR corrected cure rates in 2004 were 71%, 91%, and 94%, respectively; PCR corrected cure rates for 2006 are pending. Using treatment with SP as the baseline, the hazard ratio (95% CI) for infection was 0.26 (0.14-0.48) for SPAS and 0.14 (0.06-0.31) for Coartem; both of these were highly significant (p<0.0001). In comparison to AL, treatment with both SP and SPAS resulted in a significant increase in the hazard ratio for infection (3.6, 95% CI: 2.3-5.6 for SP and 2.2, 95% CI: 1.4- 3.5 for SPAS). Both SPAS and AL were significantly more efficacious for treatment of uncomplicated malaria than is SP. However, the efficacy of SPAS is rapidly decreasing. SP should no longer be used for treatment of malaria illness in Tanzania, either as monotherapy or as part of artemisinin combination therapy.

Table of Contents

INTRODUCTION 1 BACKGROUND 4 METHODS 10 DISCUSSION 23 CONCLUSION 29 TABLES 30 Table 1. Characteristics of enrolled patients in 2004 and 2006. 30 Table 2. Differences between enrolled patients in 2004 and 2006. 30 Table 3. Uncorrected cure rates and failure rates by type of failure for each treatment arm 31 Table 4. Geometric Mean Parasite Density (95% Confidence Interval) by Follow-up Day and Treatment Group 32 Table 5. Mean hemoglobin level, mean rise in hemoglobin, and percent of anemic children by treatment group 33 Table 6. Results of Univariate Analysis using a Cox Proportional Hazards Model 34 Table 7. Results of Multivariate Analysis using a Cox Proportional Hazards Model for 2004, showing the effect of treatment- district interaction. 35 Table 8. Results of Multivariate Analysis for 2006 using a Cox Proportional Hazards Model. 35 Table 9. Percentage of patients who owned a bed-net among those with and without new infections during the course follow-up by treatment group (2004) 35 Table 10. Side effects reported by treatment group in 2004 36 Table 11. Side effects reported by treatment group in 2006 37 Figure 1. 2004 Uncorrected failure rates stratified by treatment group 38 Figure 2. 2006 Uncorrected failure rates stratified by treatment group 39 Figure 3. Parasite clearance by treatment arm in 2004 40 Figure 4. Parasite clearance by treatment arm in 2006 40 Figure 5. Fever clearance by treatment arm, 2004 41 Figure 6. Fever clearance by treatment arm, 2006 41 REFERENCES 42

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Biology, Parasitology Health Sciences, Medicine and Surgery
Keyword	Sulfadoxine-Pyrimethamine Tanzania Artesunate malaria treatment Lumefantrine
Committee Chair / Thesis Advisor	Kachur, S. Patrick, Centers for Disease Control and Prevention
Committee Members	Boring, John R, Emory University McGowan Jr., John E, Emory University Blumberg, Henry Michael, Emory University

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