Association Between Drug Levels, Malaria, and Antimalarial Resistance in the Setting of Seasonal Malaria Chemoprevention

Study Overview
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Brief Summary
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In areas of the Sahel sub-region of Africa with intense seasonal malaria transmission, seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP+AQ) has become the standard-of-care for the prevention of malaria in children. Despite the scale-up of SMC across West Africa, the malaria burden remains high. Reasons for this are not well understood, however, it is hypothesized that children eligible for SMC who get malaria may be underdosed or may have not received SP+AQ. Moreover, there are major concerns that the continued use of the SMC strategy may increase selection of AQ and/or SP-resistant Plasmodium falciparum parasites. The overall objective of this observational study are to understand the factors driving malaria among children eligible to receive SMC and whether circulating levels of sulfadoxine (SDX), pyrimethamine (PYR), and AQ are associated with risks of malaria and antimalarial drug resistance.

Detailed Description
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In areas of the Sahel sub-region of Africa with intense seasonal malaria transmission, seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP+AQ) has become the standard-of-care for the prevention of malaria in children. Despite the scale-up of SMC across West Africa, the malaria burden remains high. Reasons for this are not well understood, however, it is hypothesized that children eligible for SMC who get malaria may be underdosed or may have not received SP+AQ. Moreover, there are major concerns that the continued use of the SMC strategy may increase selection of AQ and/or SP-resistant Plasmodium falciparum parasites. The overall objective of this observational study are to understand the factors driving malaria among children eligible to receive SMC and whether circulating levels of sulfadoxine (SDX), pyrimethamine (PYR), and AQ are associated with risks of malaria and antimalarial drug resistance. The specific objectives of this study are as follows: To determine associations between the levels of exposure to the components of SP+AQ (SDX, PYR, and AQ) and malaria risk. To determine associations between levels of exposure to the components of SP+AQ and the prevalence of P. falciparum genetic polymorphisms associated with drug resistance. To compare the prevalence of genetic polymorphisms associated with SP+AQ resistance between parasites infecting children eligible to receive SMC and those infecting older children ineligible to receive SMC. To assess whether the prevalence of genetic polymorphisms associated with SP+AQ resistance changes over time.

Official Title
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Associations Between Drug Levels and the Risk of Malaria and Drug Resistance in the Setting of Seasonal Malaria Chemoprevention in Bobo-Dioulasso, Burkina Faso

Conditions
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Malaria,Falciparum

Participation Criteria
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Eligibility Criteria
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The inclusion criteria will differ for each group enrolled into the study: Inclusion criteria for Group 1 (Children 6-59 months of age diagnosed with uncomplicated P. falciparum malaria): Aged 6-59 months Resident of health facility catchment area Provision of parental consent Fever (temperature of ≥37.5°C) or history of fever in the past 24 hours Confirmed P. falciparum parasitemia by RDT and/or microscopy Inclusion criteria for Group 2 (Children 6-59 months of age without malaria): Aged 6-59 months Resident of health facility catchment area Provision of parental consent Negative for P. falciparum parasitemia by RDT and/or microscopy Inclusion criteria for Group 3 (Children 5-10 years of age diagnosed with uncomplicated P. falciparum malaria): Aged 5-10 years Resident of health facility catchment area Provision of parental consent Fever (temperature of ≥37.5°C) or history of fever in the past 24 hours Confirmed P. falciparum parasitemia by RDT and/or microscopy The exclusion criteria for all children are as follows: Refusal to participate Residence outside of health facility catchment areas Known treatment of malaria (not SMC) in the past 14 days Danger signs (lethargy, unable to drink or breast feed, repeated vomiting, unable to stand or sit due to weakness) Signs of severe malaria, including altered conscious, respiratory distress (rapid breathing), severe anemia (<5 g/dL), or other signs of organ dysfunction. Non-malarial illness that is severe or prevents necessary study procedures

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1: Children eligible to receive SMC diagnosed with uncomplicated Plasmodium falciparum malaria<br>Children eligible to receive SMC (6-59 months of age) who were diagnosed with uncomplicated P. falciparum malaria at the health facility. | |
| Group 2: Children eligible to receive SMC presenting at health facility without malaria parasitemia<br>Group 2 will be defined as children eligible to receive SMC (6-59 months of age) who presented at the health facility and tested negative for malaria parasitemia.This group will serve as the control group to Group 1 Cases to compare the SP-AQ drug levels between children who did and did not get malaria. | |
| Group 3: Children 5-10 years of age diagnosed with uncomplicated Plasmodium falciparum malaria<br>Group 3 will be defined as children ineligible to receive SMC (5-10 years of age) who were diagnosed with uncomplicated P. falciparum malaria at the health facility. This group will serve as the control group to Group 1 Cases to compare the prevalence of SP and AQ resistance markers. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk of parasitemia | Detected by blood smear microscopy | during the seasonal SMC campaign period over three years | 
| Prevalence of antimalarial resistance markers associated with SP | Prevalence of pfdhfr and pfdhps mutations | during the seasonal SMC campaign period over three years | 
| Prevalence of antimalarial resistance markers associated with AQ | Prevalence of pfcrt and pfmdr1 mutations | during the seasonal SMC campaign period over three years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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seasonal malaria chemoprevention, sulfadoxine-pyrimethamine, amodiaquine, antimalarial resistance, pharmacokinetics, falciparum malaria, malnutrition