Artemether-lumefantrine Resistance Monitoring in Children With Uncomplicated Plasmodium Falciparum Malaria in Mali
Condition: Accute Falciparum Malaria
MeSH terms: Malaria; Malaria, Falciparum
Study type: Observational

Summary: 
      Background: Malaria is a disease caused by a parasite. People get malaria if they are bitten
      by an parasite-infected mosquito. A drug called artemether-lumefantrine (AL) can treat
      malaria. Although iAL has helped make the malaria problem less severe in the African country
      of Mali, researchers want to find out if malaria parasites are becoming resistant to this
      drug.

      Objective: To test for AL-resistant parasites in children with malaria in Mali.

      Eligibility:

      AL resistance monitoring study: children aged 2 17 years who live in Kenieroba, Mali, and
      have malaria.

      Blood collection substudy: healthy volunteers aged 18 65 years.

      Design:

      Volunteers for the substudy will have blood taken up to 6 times a year.

      Study participants will be screened with 1 finger-prick blood sample. Girls may have a
      pregnancy test.

      Baseline visit: Participants will have a physical exam. Their vital signs and temperature
      will be measured. They will answer questions about their symptoms. They will give a blood
      sample.

      Participants will get 6 doses of AL over 3 days. They will take it in tablet form with milk.

      Some participants will also stay at the clinic for 2 days. They will have a catheter placed
      in a vein. They will have blood taken frequently.

      Participants will have follow-up visits for about 1 month. They may have:

      Physical exam performed

      Vital signs and temperature measured

      Symptom questionnaire administered

      Finger-prick blood sample and/or a regular blood sample taken

      Pregnancy test given

      Antimalarial medications other than AL provided.
    

Detailed description: 
      Artemether-lumefantrine (AL) has replaced artesunate + amodiaquine as the frontline
      artemisinin (ART) combination therapy (ACT) for uncomplicated Plasmodium falciparum malaria
      in Mali. It is not known whether parasites are developing resistance to AL in Mali, where we
      are studying how naturally-acquired immunity and sickle-cell trait reduce malaria risk and
      parasite density in our pediatric study population. AL Resistance Monitoring Study: To
      monitor for emerging AL resistance in vivo and lumefantrine (LF) resistance ex vivo, we will
      conduct a standard WHO-recommended protocol to measure AL resistance rates over the next 4
      years. We will enroll all children aged 2-17 years with uncomplicated falciparum malaria and
      parasite count between 2,000 and 200,000 parasites per microliter, treat them with AL on D0,
      D1, and D2, confirm adequate LF plasma concentrations on Day 7, and monitor for malaria
      symptoms and recurrent parasitemias on D0, D1, D2, D3, D7, D14, D21, and D28. In related
      laboratory studies, we will use blood samples taken at the times of enrollment and
      recrudescence to measure parasite susceptibility to LF and other antimalarial drugs ex vivo;
      investigate genetic and transcriptional determinants of parasite response to AL in vivo and
      LF ex vivo; and prepare cryopreserved parasites for future work on drug action and resistance
      mechanisms. Parasite Clearance Substudy: We have recently discovered an agedependent
      acceleration of parasite clearance rates in Malian children, and postulate that it is
      mediated by IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1),
      the parasite s main virulence factor on the surface of infected red blood cells (iRBCs). We
      hypothesize that ART exposure induces the premature expression of PfEMP1 on the surface of
      circulating ring-iRBCs in vivo. To test this hypothesis, we will calculate parasite clearance
      rates in a subset of subjects with relatively high parasite densities, and relate these rates
      to the ability of autologous IgG to recognize ring-iRBCs over the first 8 hours of ART
      exposure in vivo. In this same subset of patients, we will also explore whether AL induces
      parasite dormancy in vivo by removing parasites at H0, H6, H24, H48, D3, D7, and D14
      following AL therapy, and cloning them to quantify the number of viable parasites. Blood
      Collection Study: We have found that sickle-cell trait (HbAS), like naturally-acquired
      humoral immunity, reduces both malaria risk and parasite density in our study population, and
      that this protection is associated with abnormal PfEMP1 display on the iRBC surface. To
      elucidate the molecular mechanism of this phenotype and explore how it may synergize with
      naturally-acquired IgG responses, we will investigate whether the development of PfEMP1
      trafficking machinery is impaired in HbAS compared to normal homozygous hemoglobin A (HbAA)
      red blood cells (RBCs). To test this, we will purify parasite isolates from children with
      malaria, inoculate them into HbAA and HbAS RBCs from healthy adult donors, and follow their
      intraerythrocytic development using flow cytometry and electron microscopy.
    

Observational model: Case-Only
Time perspective: Cross-Sectional
Keywords: Artemisinin Combination Therapy (ACT)