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<it>Pfmdr1 </it>copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia

By Wongsrichanalai Chansuda, Meshnick Steven R, Puijalon Odile, Bouchier Christiane, Bouth Denis, Yi Poravuth, Doung Socheat, Incardona Sandra, Shah Naman K, Khim Nimol, Alker Alisa P, Lim Pharath, Fandeur Thierry, Le Bras Jacques, Ringwald Pascal and Ariey Frédéric


<p>Abstract</p> <p>Background</p> <p>The combination of artesunate and mefloquine was introduced as the national first-line treatment for <it>Plasmodium falciparum </it>malaria in Cambodia in 2000. However, recent clinical trials performed at the Thai-Cambodian border have pointed to the declining efficacy of both artesunate-mefloquine and artemether-lumefantrine. Since <it>pfmdr1 </it>modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between <it>pfmdr1 </it>copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy.</p> <p>Methods</p> <p>Blood samples were collected from <it>P. falciparum</it>-infected patients enrolled in two in vivo efficacy studies in north-western Cambodia: 135 patients were treated with artemether-lumefantrine (AL group) in Sampovloun in 2002 and 2003, and 140 patients with artesunate-mefloquine (AM group) in Sampovloun and Veal Veng in 2003 and 2004. At enrollment, the in vitro IC<sub>50 </sub>was tested and the strains were genotyped for <it>pfmdr1 </it>copy number by real-time PCR.</p> <p>Results</p> <p>The <it>pfmdr1 </it>copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased <it>pfmdr1 </it>copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between <it>pfmdr1 </it>polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean <it>pfmdr1</it>copy number was lower in subjects with adequate clinical and parasitological response compared to those who experienced late treatment failure (n = 112, p < 0.001). This was not observed in the patients treated with AL (n = 96, <it>p </it>= 0.364). The presence of three or more copies of <it>pfmdr1 </it>were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR) = 7.80 [95%CI: 2.09–29.10], N = 115), <it>p </it>= 0.002) but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24–4.44], N = 109, <it>p </it>= 0.969).</p> <p>Conclusion</p> <p>This study shows that <it>pfmdr1 </it>copy number is a molecular marker of AM treatment failure in <it>falciparum </it>malaria on the Thai-Cambodian border. However, while it is associated with increased IC<sub>50 </sub>for lumefantrine, <it>pfmdr1 </it>copy number is not associated with AL treatment failure in the area, suggesting involvement of other molecular mechanisms in AL treatment failures in Cambodia.</p

Topics: Internal medicine, RC31-1245, Medicine, R, DOAJ:Internal medicine, DOAJ:Medicine (General), DOAJ:Health Sciences, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Publisher: BioMed Central
Year: 2009
DOI identifier: 10.1186/1475-2875-8-11
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