Temporal changes in Plasmodium falciparum anti-malarial drug sensitivity in vitro and resistance-associated genetic mutations in isolates from Papua New Guinea
- Author(s)
- Koleala, T; Karl, S; Laman, M; Moore, BR; Benjamin, J; Barnadas, C; Robinson, LJ; Kattenberg, JH; Javati, S; Wong, RP; Rosanas-Urgell, A; Betuela, I; Siba, PM; Mueller, I; Davis, TM;
- Journal Title
- Malaria Journal
- Publication Type
- Journal Article
- Abstract
- 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 (IC(5)(0)) >100 nM) was present in 19% of isolates. All piperaquine and naphthoquine IC(5)(0)s were <100 nM and those for lumefantrine, pyronaridine and the artemisinin derivatives were in low nM ranges. Factor analysis of IC(5)(0)s 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 IC(5)(0) 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 IC(5)(0)s 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 .
- Publisher
- BioMed Central
- Research Division(s)
- Population Health And Immunity
- PubMed ID
- 25626445
- Publisher's Version
- https://doi.org/10.1186/s12936-015-0560-3
- Open Access at Publisher's Site
http://www.malariajournal.com/content/14/1/37- NHMRC Grants
- NHMRC/1043345, NHMRC/634343,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-12-10 11:27:50
Last Modified: 2019-04-01 09:13:00