<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
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