Molecular markers of drug resistance and clinical outcome in falciparum malaria in Cambodia and the Democratic Republic of Congo Public Deposited

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  • March 21, 2019
  • Alker, Alisa P.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Background. Drug resistance is a major obstacle to the control of Plasmodium falciparum malaria. Monitoring the efficacy of antimalarials is a critical component to malaria control. One possible surveillance method is to use molecular markers. However, their relationship with clinical resistance needs to be established before they can be used. Methods. Clinical samples from an in vivo efficacy study of sulfadoxine-pyrimethamine (SP) based therapy in Rutshuru, Democratic Republic of Congo were used to estimate the effect of mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) on treatment failure. In addition, clinical samples from an in vivo efficacy study of mefloquineartesunate in Pailin, Cambodia were used to estimate the effect of changes in the P. falciparum multidrug resistance-1 (pfmdr1) gene on recrudescence. Lastly, a cross-sectional survey of Cambodia was conducted to determine the geographic distribution of the genetic changes in pfmdr1. Results. In Rutshuru, the effect of mutations at dhps-437 and dhps-540 on SP treatment failure differed by level of parasitemia: for children with low parasitemia, the presence of both mutations was associated with a 17% (95%CI: -3%, 36%) greater absolute risk of treatment failure compared to having neither mutation (baseline risk: 21%). For children with high parasitemia, the risk difference was 50% (95%CI: 35%, 64%; baseline risk: 8%). In Pailin, pfmdr1 copy number was strongly related to time to recrudescence after mefloquine-artesunate treatment (adjusted HR = 7.91, 95%CI: 2.38, 26.29). In the cross-sectional study of Cambodia, increased pfmdr1 copy number was found not only in Pailin, where mefloquine resistance has been well documented, but also in Chumkiri, an area not previously known for drug resistance. Conclusion. These studies demonstrated dhps mutations are associated with SP treatment failure in the DRC and pfmdr1 copy number is associated with recrudescence after mefloquine-artesunate treatment in Cambodia. The cross-sectional study demonstrates how the use of a molecular marker can be operationalized to detect resistant areas outside of current sentinel surveillance sites. Detecting dhps mutations in DRC and pfmdr1 copy number in Cambodia are potentially cost-effective methods to complement the current in vivo efficacy monitoring of drug resistance in these countries.
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  • Meshnick, Steven R.
  • Open access

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