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dc.contributor.authorKoleala, T.
dc.contributor.authorKarl, S.
dc.contributor.authorLaman, M.
dc.contributor.authorMoore, Brioni
dc.contributor.authorBenjamin, J.
dc.contributor.authorBarnadas, C.
dc.contributor.authorRobinson, L.
dc.contributor.authorKattenberg, J.
dc.contributor.authorJavati, S.
dc.contributor.authorWong, R.
dc.contributor.authorRosanas-Urgell, A.
dc.contributor.authorBetuela, I.
dc.contributor.authorSiba, P.
dc.contributor.authorMueller, I.
dc.contributor.authorDavis, T.
dc.identifier.citationKoleala, T. and Karl, S. and Laman, M. and Moore, B. and Benjamin, J. and Barnadas, C. and Robinson, L. et al. 2015. Temporal changes in Plasmodium falciparum anti-malarial drug sensitivity in vitro and resistance-associated genetic mutations in isolates from Papua New Guinea. Malaria Journal. 14 (1).

Background: In northern Papua New Guinea (PNG), most Plasmodium falciparum isolates proved resistant to chloroquine (CQ) in vitro between 2005 and 2007, and there was near-fixation of pfcrt K76T, pfdhfr C59R/S108N and pfmdr1 N86Y. To determine whether the subsequent introduction of artemisinin combination therapy (ACT) and reduced CQ-sulphadoxine-pyrimethamine pressure had attenuated parasite drug susceptibility and resistance-associated mutations, these parameters were re-assessed between 2011 and 2013. Methods: A validated fluorescence-based assay was used to assess growth inhibition of 52 P. falciparum isolates from children in a clinical trial in Madang Province. Responses to CQ, lumefantrine, piperaquine, naphthoquine, pyronaridine, artesunate, dihydroartemisinin, artemether were assessed. Molecular resistance markers were detected using a multiplex PCR ligase detection reaction fluorescent microsphere assay. Results: CQ resistance (in vitro concentration required for 50% parasite growth inhibition (IC50) >100 nM) was present in 19% of isolates. All piperaquine and naphthoquine IC50s were <100 nM and those for lumefantrine, pyronaridine and the artemisinin derivatives were in low nM ranges. Factor analysis of IC50s showed three groupings (lumefantrine; CQ, piperaquine, naphthoquine; pyronaridine, dihydroartemisinin, artemether, artesunate). Most isolates (96%) were monoclonal pfcrt K76T (SVMNT) mutants and most (86%) contained pfmdr1 N86Y (YYSND). No wild-type pfdhfr was found but most isolates contained wild-type (SAKAA) pfdhps. Compared with 2005-2007, the geometric mean (95% CI) CQ IC50 was lower (87 (71-107) vs 167 (141-197) nM) and there had been no change in the prevalence of pfcrt K76T or pfmdr1 mutations. There were fewer isolates of the pfdhps (SAKAA) wild-type (60 vs 100%) and pfdhfr mutations persisted. Conclusions: Reflecting less drug pressure, in vitro CQ sensitivity appears to be improving in Madang Province despite continued near-fixation of pfcrt K76T and pfmdr1 mutations. Temporal changes in IC50s for other anti-malarial drugs were inconsistent but susceptibility was preserved. Retention or increases in pfdhfr and pfdhps mutations reflect continued use of sulphadoxine-pyrimethamine in the study area including through paediatric intermittent preventive treatment. The susceptibility of local isolates to lumefantrine may be unrelated to those of other ACT partner drugs. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000913077.

dc.publisherBioMed Central
dc.titleTemporal changes in Plasmodium falciparum anti-malarial drug sensitivity in vitro and resistance-associated genetic mutations in isolates from Papua New Guinea
dc.typeJournal Article
dcterms.source.titleMalaria Journal

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curtin.departmentSchool of Pharmacy
curtin.accessStatusOpen access

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