Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms
Background. Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined. Methods. Using a modified schizont maturati...
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th-mahidol.239702018-08-24T08:39:54Z Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms Rossarin Suwanarusk Bruce Russell Marina Chavchich Ferryanto Chalfein Enny Kenangalem Varakorn Kosaisavee Budi Prasetyorini Kim A. Piera Marion Barends Alan Brockman Usa Lek-Uthai Nicholas M. Anstey Emiliana Tjitra François Nosten Qin Cheng Ric N. Price Charles Darwin University Australian Army Malaria Institute Badan Penelitian Dan Pengembangan Kesehatan, Kementerian Kesehatan Republik Indonesia District Ministry of Health Mahidol University Shoklo Malaria Research Unit John Radcliffe Hospital Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology Background. Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined. Methods. Using a modified schizont maturation assay we investigated the in vitro chloroquine susceptibility profile and molecular polymorphisms of P. vivax isolates collected from Papua, Indonesia, where high levels of clinical chloroquine treatment failure have been reported, and from Thailand, where chloroquine treatment is generally effective. Results. The geometric mean chloroquine IC50for P. vivax isolates from Papua (n=145) was 312 nM [95%Cl: 237-411 nM] compared to 46.8 nM [95%Cl: 34.7-63.1 nM] from Thailand (n = 81); p<0.001. Correlating with the known clinical efficacy of the area, a cut off for chloroquine resistance was defined as 220nM, a level exceeded in 13.6% (11/81) of Thai isolates and 65% (94/145) of Papuan isolates; p<0.001. Several sequence polymorphisms in pvcrt-o and pvmdr1, and difference in pvmdr1 copy number were identified. A Y976F mutation in pvmdr1 was present in 96% (123/128) of Papuan isolates and 25% (17/69) of Thai isolates; p<0.001. Overall, the geometric mean chloroquine IC50in isolates with the Y976F mutation was 283 nM [95%Cl: 211-379], compared to 44.5 nM [95%Cl: 31.3-63.4] in isolates with the wild type; p< 0.001. Pvmdr1 amplification occurred in 23% (15/66) of Thai isolates compared to none (0/104) of Indonesian isolates (p<0.001), but was not associated with increased chloroquine resistance after controlling for geographical location. Conclusions. In vitro susceptibility testing of P. vivax discriminates between populations with differing levels of clinical efficacy of chloroquine. The pvmdr1 polymorphism at Y976F may provide a useful tool to highlight areas of emerging chloroquine resistance, although further studies defining its clinical correlates are needed. © 2007 Suwanarusk et al. 2018-08-24T01:36:58Z 2018-08-24T01:36:58Z 2007-10-31 Article PLoS ONE. Vol.2, No.10 (2007) 10.1371/journal.pone.0001089 19326203 2-s2.0-40549103634 https://repository.li.mahidol.ac.th/handle/123456789/23970 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=40549103634&origin=inward |
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Agricultural and Biological Sciences Biochemistry, Genetics and Molecular Biology Rossarin Suwanarusk Bruce Russell Marina Chavchich Ferryanto Chalfein Enny Kenangalem Varakorn Kosaisavee Budi Prasetyorini Kim A. Piera Marion Barends Alan Brockman Usa Lek-Uthai Nicholas M. Anstey Emiliana Tjitra François Nosten Qin Cheng Ric N. Price Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms |
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Background. Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined. Methods. Using a modified schizont maturation assay we investigated the in vitro chloroquine susceptibility profile and molecular polymorphisms of P. vivax isolates collected from Papua, Indonesia, where high levels of clinical chloroquine treatment failure have been reported, and from Thailand, where chloroquine treatment is generally effective. Results. The geometric mean chloroquine IC50for P. vivax isolates from Papua (n=145) was 312 nM [95%Cl: 237-411 nM] compared to 46.8 nM [95%Cl: 34.7-63.1 nM] from Thailand (n = 81); p<0.001. Correlating with the known clinical efficacy of the area, a cut off for chloroquine resistance was defined as 220nM, a level exceeded in 13.6% (11/81) of Thai isolates and 65% (94/145) of Papuan isolates; p<0.001. Several sequence polymorphisms in pvcrt-o and pvmdr1, and difference in pvmdr1 copy number were identified. A Y976F mutation in pvmdr1 was present in 96% (123/128) of Papuan isolates and 25% (17/69) of Thai isolates; p<0.001. Overall, the geometric mean chloroquine IC50in isolates with the Y976F mutation was 283 nM [95%Cl: 211-379], compared to 44.5 nM [95%Cl: 31.3-63.4] in isolates with the wild type; p< 0.001. Pvmdr1 amplification occurred in 23% (15/66) of Thai isolates compared to none (0/104) of Indonesian isolates (p<0.001), but was not associated with increased chloroquine resistance after controlling for geographical location. Conclusions. In vitro susceptibility testing of P. vivax discriminates between populations with differing levels of clinical efficacy of chloroquine. The pvmdr1 polymorphism at Y976F may provide a useful tool to highlight areas of emerging chloroquine resistance, although further studies defining its clinical correlates are needed. © 2007 Suwanarusk et al. |
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Charles Darwin University |
author_facet |
Charles Darwin University Rossarin Suwanarusk Bruce Russell Marina Chavchich Ferryanto Chalfein Enny Kenangalem Varakorn Kosaisavee Budi Prasetyorini Kim A. Piera Marion Barends Alan Brockman Usa Lek-Uthai Nicholas M. Anstey Emiliana Tjitra François Nosten Qin Cheng Ric N. Price |
format |
Article |
author |
Rossarin Suwanarusk Bruce Russell Marina Chavchich Ferryanto Chalfein Enny Kenangalem Varakorn Kosaisavee Budi Prasetyorini Kim A. Piera Marion Barends Alan Brockman Usa Lek-Uthai Nicholas M. Anstey Emiliana Tjitra François Nosten Qin Cheng Ric N. Price |
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Rossarin Suwanarusk |
title |
Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms |
title_short |
Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms |
title_full |
Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms |
title_fullStr |
Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms |
title_full_unstemmed |
Chloroquine resistant Plasmodium vivax: In vitro characterisation and association with molecular polymorphisms |
title_sort |
chloroquine resistant plasmodium vivax: in vitro characterisation and association with molecular polymorphisms |
publishDate |
2018 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/23970 |
_version_ |
1763488123346485248 |