Artemisinin-resistant, Drug Resistance, Ethiopia, Malaria (Plasmodium Falciparum)
Conditions
Keywords
Artemisinin partial resistance, Plasmodium falciparum, Pfkelch13, Ring-stage survival assay, Day-3 positivity, Ethiopia, Artemether-lumefantrine, Antimalarial drug resistance
Brief summary
Artemisinin-based combination therapies (ACTs) are the main treatment for falciparum malaria in Africa. Artemisinin partial resistance (ART-R), characterized by delayed parasite clearance after treatment, has been confirmed in four sub-Saharan African countries. In Ethiopia, molecular surveys have detected the Pfkelch13 R622I mutation associated with ART-R at multiple sites, but no study has yet combined clinical, molecular, and in vitro evidence to confirm ART-R per WHO criteria. This multisite study conducted across five sentinel sites in Ethiopia (2024-2025) assessed day-3 parasite positivity after artemether-lumefantrine treatment, Pfkelch13 genotyping, and ring-stage survival assay on culture-adapted field isolates, to determine whether ART-R is confirmed in Ethiopian Plasmodium falciparum populations.
Detailed description
This study integrated three WHO-required lines of evidence to confirm artemisinin partial resistance (ART-R) in Ethiopia: (1) clinical evidence through day-3 parasite positivity assessment after artemether-lumefantrine treatment in therapeutic efficacy studies; (2) molecular evidence through Pfkelch13 propeller domain genotyping; and (3) phenotypic in vitro evidence through ring-stage survival assay (RSA0-3h) on culture-adapted field isolates. Five sentinel sites were selected across malaria-endemic regions of Ethiopia. Blood samples were collected at enrollment (day 0) and day 3. Isolates were cryopreserved and shipped to France (Strasbourg) for RSA.
Interventions
Artemether-lumefantrine (Coartem) administered orally twice daily for 3 days at weight-based dosing per Ethiopian national malaria treatment guidelines.
Sponsors
Didier Menard
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Single-arm therapeutic efficacy study. All enrolled patients with uncomplicated Plasmodium falciparum malaria received artemether-lumefantrine (AL) per Ethiopian national treatment guidelines. Clinical, molecular, and in vitro outcomes were assessed to determine whether artemisinin partial resistance meets WHO confirmation criteria.
Eligibility
Sex/Gender
ALL
Age
6 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 6 months * Microscopically confirmed uncomplicated Plasmodium falciparum monoinfection * Axillary temperature ≥ 37.5°C or history of fever in the past 24 hours * Ability to take oral medication * Written informed consent from patient or parent/guardian * Residence in the study area with intention to remain during follow-up
Exclusion criteria
* Severe or complicated malaria (WHO criteria) * Mixed Plasmodium infection * Pregnancy or breastfeeding * Known hypersensitivity to artemether-lumefantrine * Antimalarial treatment in the 4 weeks prior to enrollment * Severe malnutrition * Concomitant febrile illness other than malaria requiring systemic treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day-3 Parasite Positivity Rate | Day 3 (72 hours after treatment initiation) | Proportion of patients with microscopically detectable Plasmodium falciparum parasitaemia on day 3 (72 ± 2 hours) after initiation of artemether-lumefantrine treatment, assessed by Giemsa-stained thick blood smear examination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of Pfkelch13 R622I Mutation | Day 0 (enrollment) | Proportion of day-0 samples carrying the validated Pfkelch13 R622I mutation, assessed by targeted amplicon sequencing. |
| Ring-Stage Survival Rate | Assessed on culture-adapted isolates collected at Day 0 | In vitro survival rate of culture-adapted field isolates after 6-hour exposure to 700 nM dihydroartemisinin, assessed by ring-stage survival assay (RSA0-3h). Resistance threshold: survival rate \>1%. |
Countries
Ethiopia
Contacts
PRINCIPAL_INVESTIGATORDidier Menard, Professor
University Hospital, Strasbourg, France
Outcome results
None listed