Spatiotemporal Dynamics of Antimalarial Drug Resistance in Western Kenya During a Pilot Multiple First-line Treatment for Uncomplicated Malaria Study: Molecular Evidence of Resistance Saturation and Emerging Artemisinin Tolerance
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 316
- 试验地点
- 2
- 主要终点
- Health Systems Feasibility - Commodity Management Score
研究概览
简要总结
This implementation study evaluated the health systems feasibility, economic costs, and stakeholder acceptability of deploying multiple first-line therapies (MFTs) that were of the artemisinin-based combination therapies (ACTs) type, for uncomplicated malaria in Western Kenya. The study included a nested observational molecular surveillance of antimalarial resistance markers in Plasmodium falciparum parasites. The implementation program involved adaptive cycling of four ACTs across 28 health facilities over 28 months (June 2020 - October 2022) with and extension to January 2024 in one geographic area (Mfangano Island). Health systems outcomes (feasibility, costs, acceptability) are reported in Cole et al., Malaria Journal 2024. Molecular surveillance outcomes (resistance marker prevalence and temporal trends) are reported in a companion manuscript currently under peer-review.
详细描述
BACKGROUND: Artemisinin-based combination therapies (ACTs) are first-line treatment for uncomplicated malaria in sub-Saharan Africa, but emerging artemisinin partial resistance threatens efficacy. Multiple first-line treatments (MFTs) represent a proposed strategy to delay resistance emergence by deploying several ACTs simultaneously, sequentially, or using other strategies rather than relying on a single first-line therapy.
STUDY DESIGN: This 28-month implementation program (June 2020 - October 2022) with and extension only on Mfangano Island until January 2024, deployed adaptive cycling of four artemisinin-based combinations across health facilities in Western Kenya using geographic allocation:
INTERVENTION COUNTY - HOMA BAY:
- Homa Bay Mainland (n=approximately 40,000 patients treated): Sequential deployment with 8-month cycling using crowding-out approach: Baseline (AL) → DHA-PIP (8 months) → AS+AQ (8 months) → AL (8 months)
- Mfangano Island (n=approximately 21,000 patients treated): Extended single MFT deployment: Baseline (AL) → AS+PYD (39 months). This extension allowed longer follow-up surveillance of the most recent combination ACT in Kenya where data was not previously monitored.
COMPARISON COUNTY - MIGORI:
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Other
入排标准
- 年龄范围
- 5 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 5 years or older
- •Clinical diagnosis of uncomplicated malaria
- •Confirmed Plasmodium falciparum infection by rapid diagnostic test (RDT) or microscopy
- •Presenting at participating health facility for malaria treatment
- •Able and willing to provide informed consent (or parental/guardian consent for minors under 18 years)
- •Resident of study catchment area
- •For molecular surveillance substudy: willingness to provide dried blood spot sample
排除标准
- •Pregnant women (due to contraindications for some study medications in first trimester and lack of safety data)
- •Children under 5 years of age (due to lack of pediatric formulations for some study medications)
- •Severe or complicated malaria requiring parenteral treatment or hospitalization
- •Known hypersensitivity or contraindication to any of the study artemisinin-based combination therapies
- •Unable to take oral medications
- •Previous participation in current treatment episode (repeat visits)
- •Concurrent participation in other interventional malaria treatment studies
研究组 & 干预措施
Homa Bay Mainland: MFT Adaptive Cycling
Sequential deployment of multiple first-line artemisinin-based combination therapies using 8-month adaptive cycling with crowding-out approach. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by dihydroartemisinin-piperaquine (DHA-PIP) for 8 months, then artesunate-amodiaquine (AS+AQ) for 8 months, then return to AL for 8 months. Approximately 40,000 patients treated across multiple health facilities. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
干预措施: Artemether + Lumefantrine (Drug)
Homa Bay Mainland: MFT Adaptive Cycling
Sequential deployment of multiple first-line artemisinin-based combination therapies using 8-month adaptive cycling with crowding-out approach. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by dihydroartemisinin-piperaquine (DHA-PIP) for 8 months, then artesunate-amodiaquine (AS+AQ) for 8 months, then return to AL for 8 months. Approximately 40,000 patients treated across multiple health facilities. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
干预措施: Dihydroartemisin-piperaquine (Drug)
Homa Bay Mainland: MFT Adaptive Cycling
Sequential deployment of multiple first-line artemisinin-based combination therapies using 8-month adaptive cycling with crowding-out approach. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by dihydroartemisinin-piperaquine (DHA-PIP) for 8 months, then artesunate-amodiaquine (AS+AQ) for 8 months, then return to AL for 8 months. Approximately 40,000 patients treated across multiple health facilities. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
干预措施: Artesunate-Amodiaquine (AS-AQ) (Drug)
Mfangano Island: MFT Extended Deployment
Extended deployment of a single alternative artemisinin-based combination therapy in a geographically isolated island setting. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by pyronaridine-artesunate (AS+PYD) for extended 39-month period. Approximately 21,000 patients treated. This arm assessed health systems feasibility and molecular resistance dynamics with prolonged single MFT deployment in a relatively closed transmission environment since minimal data was available owing to AS+PYD recency of formulary inclusion. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
干预措施: Pyronaridine - artesunate (Drug)
Mfangano Island: MFT Extended Deployment
Extended deployment of a single alternative artemisinin-based combination therapy in a geographically isolated island setting. Treatment sequence: Baseline artemether-lumefantrine (AL) followed by pyronaridine-artesunate (AS+PYD) for extended 39-month period. Approximately 21,000 patients treated. This arm assessed health systems feasibility and molecular resistance dynamics with prolonged single MFT deployment in a relatively closed transmission environment since minimal data was available owing to AS+PYD recency of formulary inclusion. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
干预措施: Artemether + Lumefantrine (Drug)
Migori: Control
Continued artemether-lumefantrine (AL) as the only ACT throughout the entire study period as per Kenya national malaria treatment guidelines. Served as comparison group for health systems outcomes and molecular resistance surveillance. Approximately 32,835 patients treated. This arm represents standard of care without MFT intervention. Note: This observational molecular surveillance study analyzed resistance markers from samples collected during MFT deployment by health authorities (described in Reference 34). Arms represent different drug deployment contexts in which molecular surveillance was conducted. No intervention by research team; observational analysis only.
干预措施: Artemether + Lumefantrine (Drug)
结局指标
主要结局
Health Systems Feasibility - Commodity Management Score
时间窗: June 2020 to January 2024
Assessment of drug supply chain functionality including quantification accuracy, stock management, and distribution logistics. Measured using structured health facility assessment checklist scoring five domains: (1) drug availability, (2) stock-out frequency, (3) quantification accuracy, (4) storage conditions, (5) distribution timeliness. Score range 0-100 where higher scores indicate better commodity management. Assessed at 28 health facilities.
Health Systems Feasibility - Human Resources and Information Systems Score
时间窗: June 2020 to January 2024
Assessment of human resources adequacy and health information system functionality. Measured using structured facility assessment scoring: (1) healthcare worker availability, (2) training completion rates, (3) reporting tool adoption, (4) KHIS2 system functionality. Score range 0-100 where higher scores indicate better health systems capacity. Assessed at 28 health facilities.
Stakeholder Acceptability - Composite Acceptability Score
时间窗: June 2020 - January 2024
Composite measure of MFT deployment acceptability among three stakeholder groups: policymakers, healthcare workers, and patients. Measured through: (1) key informant interviews (n=85) using semi-structured guides rated on 5-point Likert scale, (2) patient exit interviews assessing treatment satisfaction (5-point scale), (3) healthcare worker surveys assessing implementation feasibility (5-point scale). Composite score calculated as mean across all stakeholder groups. Range 1-5 where higher scores indicate greater acceptability.
Economic Costs of Multiple First-Line Treatment Implementation
时间窗: June 2020 to January 2024
Total economic costs of MFT deployment calculated using activity-based costing approach with ingredient method. Includes start-up phase costs (training, IEC materials, reporting tool revision, KHIS2 updates, sensitization) and implementation phase costs (drug procurement, distribution, refresher training, quantification). Costs tracked prospectively from documents, receipts, and market prices. Reported as: (1) total economic vs financial costs in USD, (2) costs by category, (3) costs by funding source, (4) unit cost per facility covered in USD, (5) unit cost per patient treated in USD. Start-up costs annualized over 3-year useful life at 3% discount rate.
次要结局
- Prevalence of Antimalarial Resistance Markers(September 2020 to January 2024)
- Change in Antimalarial Resistance Marker Prevalence Over Time (Cochran-Armitage Trend Test)(Four time-points over 40 months: T1 (September 2020), T2 (August - October 2021), T3 (May - July 2022), T4 (November 2023 - January 2024))
- Geographic Distribution of Antimalarial Resistance Markers(September 2020 - January 2024)
- Complexity of Infection in Plasmodium falciparum(September 2020 - January 2024)
研究者
Andrew Cole
Research Scientist
Strathmore University