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            <funder>This work was supported by the Institut Pasteur du Cambodge and by USAID and BMGF grants through the WHO. W.R.J.T. was supported (from October 2013 to October 2014) by France Expertise International under the 5% initiative.</funder>
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              <classCode scheme="mesh">Treatment Failure</classCode>
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              <p>Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance. Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine (PP), the latest of the artemisinin-based combination therapies (ACTs) recommended by the WHO, have prompted further investigations. The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days. Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine, polymorphisms in the K13 gene, and the copy number of the Pfmdr-1 gene. A total of 425 patients were recruited in 2011 to 2013. The proportion of patients with recrudescent infections was significantly higher in western (15.4%) than in eastern (2.5%) Cambodia (P &lt;10(-3)). Day 7 plasma PP concentrations and median 50% inhibitory concentrations (IC50) of PP were independent of treatment outcomes, in contrast to median mefloquine IC50, which were found to be lower for isolates from patients with recrudescent infections (18.7 versus 39.7 nM; P = 0.005). The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele (odds ratio [OR], 17.5; 95% confidence interval [CI], 1 to 308; P = 0.04). Our data show evidence of P. falciparum resistance to PP in western Cambodia, an area of widespread artemisinin resistance. New therapeutic strategies, such as the use of triple ACTs, are urgently needed and must be tested. (This study has been registered at the Australian New Zealand Clinical Trials Registry under registration no. ACTRN12614000344695.).</p>
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              <org type="consortium">We thank the patients for agreeing to take part in these studies. We are also grateful to the provincial health directors and the local health staff at the study sites.</org>
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        </org>
        <org type="regrouplaboratory" xml:id="struct-1613461" status="VALID">
          <orgName>Organisation Mondiale de la Santé - World Health Organization Regional Office for the Western Pacific</orgName>
          <orgName type="acronym">OMS / WHO WPRO</orgName>
          <desc>
            <address>
              <addrLine>P.O. Box 2932, 1000 Manila, Philippines</addrLine>
              <country key="PH"/>
            </address>
            <ref type="url">https://www.who.int/westernpacific</ref>
          </desc>
          <listRelation>
            <relation active="#struct-548010" type="direct"/>
          </listRelation>
        </org>
        <org type="institution" xml:id="struct-302612" status="VALID">
          <idno type="ROR">https://ror.org/052gg0110</idno>
          <orgName>University of Oxford</orgName>
          <desc>
            <address>
              <addrLine>Wellington Square, Oxford OX1 2JD</addrLine>
              <country key="GB"/>
            </address>
            <ref type="url">http://www.ox.ac.uk/</ref>
          </desc>
        </org>
        <org type="institution" xml:id="struct-303866" status="VALID">
          <orgName>Mahidol University [Bangkok]</orgName>
          <desc>
            <address>
              <addrLine>999 Phuttamonthon 4 Road, Salaya, Nakhon Pathom 73170 Thailand</addrLine>
              <country key="TH"/>
            </address>
            <ref type="url">https://mahidol.ac.th/</ref>
          </desc>
        </org>
        <org type="regrouplaboratory" xml:id="struct-544003" status="VALID">
          <orgName>Nuffield Department of Medicine [Oxford, UK]</orgName>
          <orgName type="acronym">Big Data Institute</orgName>
          <desc>
            <address>
              <addrLine>Oxford, OX3 7BN.</addrLine>
              <country key="GB"/>
            </address>
          </desc>
          <listRelation>
            <relation active="#struct-302612" type="direct"/>
          </listRelation>
        </org>
        <org type="regroupinstitution" xml:id="struct-301247" status="VALID">
          <orgName>Pasteur Network (Réseau International des Instituts Pasteur)</orgName>
          <desc>
            <address>
              <addrLine>25, rue du Dr Roux 75724 Paris Cedex 15</addrLine>
              <country key="FR"/>
            </address>
            <ref type="url">https://pasteur-network.org/</ref>
          </desc>
        </org>
      </listOrg>
    </back>
  </text>
</TEI>