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Background  The combination of artesunate and mefloquine was introduced as the national first-line treatment for  Plasmodium falciparum  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  pfmdr1  modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between  pfmdr1  copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy.    Methods  Blood samples were collected from  P. falciparum -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 50  was tested and the strains were genotyped for  pfmdr1  copy number by real-time PCR.    Results  The  pfmdr1  copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased  pfmdr1  copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between  pfmdr1  polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean  pfmdr1 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,  p  = 0.364). The presence of three or more copies of  pfmdr1  were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR) = 7.80 [95%CI: 2.09–29.10], N = 115),  p  = 0.002) but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24–4.44], N = 109,  p  = 0.969).    Conclusion  This study shows that  pfmdr1  copy number is a molecular marker of AM treatment failure in  falciparum  malaria on the Thai-Cambodian border. However, while it is associated with increased IC 50  for lumefantrine,  pfmdr1  copy number is not associated with AL treatment failure in the area, suggesting involvement of other molecular mechanisms in AL treatment failures in Cambodia.

Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia