Quantifying Antimalarial Drug Pressure And Assessing Implications On Drug Resistance Patterns: An Ecologic Study Restricted; Files Only
Bako, Ruth (Spring 2025)
Abstract
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) for uncomplicated Plasmodium falciparum malaria. Overdependence on a single ACT increases pressure and the subsequent risk of selection and spread of resistant parasite strains, reducing treatment effectiveness.
In this ecologic study, data from household surveys in 29 malaria-endemic African countries over the last two decades (2003–2023) were retrospectively examined to assess ACT use by region (East, West, Central) and period. ACT use rates were compared with the prevalence of WHO-validated resistance polymorphisms in the Pfk13 genes, from molecular surveillance studies of P. falciparum parasites within the same period by region. Data tracked temporal shifts in drug resistance markers, aligning with key historical malaria treatment events such as the introduction of ACTs in 2003.
ACT use surged over the past two decades. Between 2003–2013 and 2014–2023, the median proportion of children with fever under the age of five receiving ACTs rose from 54.4% (28.8, 69.5) to 90.2% (85.0, 93.2) in East Africa; 32.0% (18.7, 46.1) to 48.5% (28.9, 78.2) in West Africa; and 21.6% (12.0, 39.5) to 45.7% (21.2, 56.1) in Central Africa. In the same period, validated Pfk13 mutations showed an increase in East and Central Africa, with East Africa experiencing the highest rise in median prevalence from 0.7% (0.4, 1.8) to 3.3% (2.2, 6.7) while in Central Africa, prevalence rose from 0.0% (0, 0) to 2.2% (1.2, 3.3). Conversely, in West Africa, there was a slight decline in prevalence, from 3.1% (2.3, 3.9) to 2.6% (2.6, 2.6).
Overall, across both periods, countries with reported resistance markers had higher overall median ACT consumption than those without. In 2003–2013, consumption was 42.1% (33.5, 59.6) in countries with resistance markers, compared to 35.5% (24.7, 50.1) in those without. This gap widened in 2014–2023, with median consumption reaching 82.1% (75.4, 89.1) in countries with identified resistance markers versus 55.3% (36.1, 76.8) in countries without. However, this relationship varied when examined at the regional level.
Findings highlight evolving antimalarial drug resistance patterns and emphasize the need for continuous molecular surveillance to inform treatment policies and sustain the efficacy of antimalarial treatment.
Table of Contents
1. INTRODUCTION
2. LITERATURE REVIEW
2.1 Background
2.2 The Concept of Drug Pressure in Antimalarial Resistance Development
2.3 Historical and Contemporary Trends in Antimalarial Drug Resistance
2.4 Evidence Linking Drug Pressure to Resistance Patterns
2.5 Methods for Measuring Drug Pressure and Resistance
2.6 Gaps in Research and Justification for this Study
3. METHODOLOGY
3.1 Selection and inclusion of data
3.1.1 The Demographic and Health Surveys (DHS) and Malaria Indicator Surveys (MIS)
3.1.2 The WorldWide Antimalarial Resistance Network (WWARN) Database
3.2 Definition of Artemisinin Partial Resistance and Validated Markers of Mutation
3.3 Statistical Analysis
3.3.1 Description of data sources
3.3.2 The Prevalence of ACT Consumption at the Population Level
3.3.3 The Prevalence and Distribution of Molecular Markers of Artemisinin Resistance
3.3.4 The Relationship Between ACT Consumption and Artemisinin Resistance Prevalence
3.4 Ecologic Nature of the Study
3.5 Exclusion of Missing Values
3.6 Ethics statement
4. RESULTS
5. DISCUSSION
5.1 Key findings
5.1.1 ACT Consumption
5.1.2 Resistance Prevalence
5.1.3 Association between ACT consumption and resistance prevalence
5.2 Implications of Findings
5.3 Limitations
5.4 Future Research Directions and Recommendations
5.5 Conclusion
6. REFERENCES
7. TABLES AND FIGURES
Table 1: Description of data sources
Table 2. Consumption of ACTs at population level by Geographic Region and Year
Table 3: Prevalence of validated and candidate or associated PfK13 markers of artemisinin partial resistance in reviewed studies by Geographic Region and Year
Figure 1: Distribution of Artemisinin Resistance Markers (WHO Validated and Candidate or Associated) in Africa
Figure 2: Allelic frequency of validated mutations in the PfK13 gene
Figure 3: ACT consumption by Year, comparing regions with no resistance marker versus resistance markers present
Figure 4: ACT consumption by Geographic Region and Year, comparing countries with no resistance marker versus resistance marker present
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