The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance

Study Overview
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Brief Summary
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The newly introduced antimalarial drug artemether-lumefantrine is currently recommended as second line antimalarial in Sudan. Recurrent infection after treatment with this drug has been associated with selection of certain genes in the malaria parasite. However there is no information on this association in Sudan.This study is going to look into the genetics of resistance to artemether-lumefantrine.

Detailed Description
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In Sudan the current treatment protocol includes two artemisinin combinations (ACT); artesunate + sulphadoxine/pyrimethamine (AS/SP) as first line and artemether-lumefantrine (AL) as second line. This protocol has been implemented in 2004, since then various studies have reported the high efficacy of both combinations (e.g. Adam et al., 2005; Elamin et al., 2005; Mohamed et al., 2006). However, there has been no report of the impact of these combinations on drug resistance markers in Sudan. Data from other African countries has shown that AL selects for certain alleles in the pfmdr-1 gene (Sisowath et al., 2005, Dokomajilar et al., 2006; Humphreys et al., 2007), but the impact on the prevalence of different pfcrt and pfmdr-1alleles remains unclear. It is essential to monitor ACT efficacy in addition to identify molecular markers that are associated with response to different drugs to facilitate epidemiological surveys for evidence based decision making. Recent work in The Gambia suggests that transmission-related endpoints, such as emergence of gametocytes after treatment, may be better indicators of emerging drug resistance (Hallett et al., 2006). The aim of the proposed study is to examine the impact of treatment with artemether-lumefantrine (AL) on alleles of pfcrt and pfmdr-1 in P. falciparum isolates in an area of marked seasonal transmission in eastern Sudan. Most studies of resistance markers measure marker prevalence by DNA amplification, but we will also investigate gene expression using quantitative amplification of mRNA encoding pfcrt and pfmdr-1. The impact of genotype and gene expression levels on treatment outcome, and on the emergence and density of peripheral gametocytes will be examined.

Official Title
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The Impact of Artemether-Lumefantrine on Genes Associated With Antimalarial Resistance in an Area of Seasonal Transmission

Conditions
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Falciparum Malaria, Antimalarials

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mono-infection with P. falciparum by microscopy. Initial parasite density of 1000 to 100,000 asexual parasites/µl. Absence of general danger signs or other signs of severe and complicated falciparum malaria according to WHO definitions. Informed consent provided by patient or parent/guardian. Exclusion Criteria: Pregnancy Infection with mixed Plasmodium sp. Signs of severe malaria or any danger signs Refusal to provide consent

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| AL<br>Cohort of study participants receiving treatment with artemether-lumefantrine | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of expression of pfcrt and pfmdr-1 alleles on day 0, 3, 7, 14, 21, 28 detected by real-time PCR. |  | 2007 to 2009 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasitological failure occurring at day 3, 7, 14, 21, 28 or any other day during this period. |  | within 28 days of subject recruitment | 
| Gametocyte development detected by reverse transcriptase PCR on day 0, 3, 14 and 28 |  | 2008 to 2009 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artemether-lumefantrine, Plasmodium falciparum, drug resistance genes