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Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms

Suwanarusk, Rossarin, Russell, Bruce, Chavchich, Marina, Chalfein, Ferryanto, Kenangalem, Enny, Kosaisavee, Varakom, Prasetyorini, Budi, Piera, Kim A., Barends, Marion, Brockman, Alan, Lek-Uthai, Usa, Anstey, Nicholas M., Tjitra, Emiliana, Nosten, Francois, Cheng, Qin and Price, Ric N. (2007). Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms. PLoS ONE,2(10):e1089.

Document type: Journal Article
Citation counts: Scopus Citation Count Cited 58 times in Scopus Article | Citations

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Title Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms
Author Suwanarusk, Rossarin
Russell, Bruce
Chavchich, Marina
Chalfein, Ferryanto
Kenangalem, Enny
Kosaisavee, Varakom
Prasetyorini, Budi
Piera, Kim A.
Barends, Marion
Brockman, Alan
Lek-Uthai, Usa
Anstey, Nicholas M.
Tjitra, Emiliana
Nosten, Francois
Cheng, Qin
Price, Ric N.
Journal Name PLoS ONE
Publication Date 2007
Volume Number 2
Issue Number 10
ISSN 1932-6203   (check CDU catalogue  open catalogue search in new window)
Scopus ID 2-s2.0-40549103634
Start Page e1089
Total Pages 9
Place of Publication San Francisco, United States of America
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DEST)
Abstract 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 IC50 for P. vivax isolates from Papua (n = 145) was 312 nM [95%CI: 237–411 nM] compared to 46.8 nM [95%CI: 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 IC50 in isolates with the Y976F mutation was 283 nM [95%CI: 211–379], compared to 44.5 nM [95%CI: 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.
Keywords treatment failure of chloroquine
P. vivax infections
Indonesia
DOI http://dx.doi.org/10.1371/journal.pone.0001089   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)


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