Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999–2009
Julien Zwang,Grant Dorsey,Andreas Mårtensson,Umberto D'Alessandro,Jean Louis Ndiaye,Corine Karema,Abdoulaye Djimde,Philippe Brasseur,Sodiomon B. Sirima,Piero Olliaro +9 more
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TLDR
Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ, and the prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling.Abstract:
Artemisinin-based combination therapy (ACT) is the recommended first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide but decreased artemisinin susceptibility, phenotypically characterized as slow parasite clearance time (PCT), has now been reported in Southeast Asia. This makes it all too important to measure the dynamics of parasite clearance in African patients treated with ACT over time, to understand trends and detect changes early enough to intervene Individual patient data from 27 clinical trials of artesunate-amodiaquine (ASAQ) vs comparators conducted between 1999 and 2009 were analysed for parasite clearance on modified intent-to-treat (ITT) basis. Overall 15,017 patients treated for uncomplicated P. falciparum malaria at 44 sites in 20 sub-Saharan African countries were included in the analysis; 51% (n=7,660) vs 49% (n=7,357) were treated with ASAQ and comparator treatments, respectively. Seventy-seven per cent (77%) were children under six years of age. The proportion of the patients treated with ASAQ with persistent parasitaemia on Day 2 was 8.6%, and 1.5% on Day 3. Risk factor for not clearing parasites on Day 2 and Day 3 calculated by multivariate logistic regression with random effect on site and controlling for treatment were: high parasitaemia before treatment was (adjusted risk ratios (AOR) 2.12, 95% CI 1.91-2.35, AOR 2.43, 95% CI 1.98-3.00, respectively); non-ACT treatment (p=0.001, for all comparisons). Anaemia (p=0.001) was an additional factor for Day 2 and young age (p=0.005) for Day 3. In patients treated with ASAQ in studies who had complete parasitaemia data every 24 hours up to Day 3 and additionally Day 7, the parasite reduction ratio was 93.9% by Day 1 and 99.9% by Day 2. Using the median parasitaemia before treatment (p0=27,125 μL) and a fitted model, the predicted PCT (pPCT = 3.614*ln (p0) – 6.135, r² = 0.94) in ASAQ recipients was 31 hours. Within the period covered by these studies, rapid Plasmodium falciparum clearance continues to be achieved in Sub-Saharan African patients treated with ACT, and in particular with ASAQ. The prediction formula for parasite clearance time could be a pragmatic tool for studies with binary outcomes and once-daily sampling, both for research and monitoring purposes.read more
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References
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Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp,François Nosten,Poravuth Yi,Debashish Das,Aung Phae Phyo,Joel Tarning,Khin Maung Lwin,Frédéric Ariey,Warunee Hanpithakpong,Sue J. Lee,Pascal Ringwald,Kamolrat Silamut,Mallika Imwong,Kesinee Chotivanich,Pharath Lim,Trent Herdman,Sen Sam An,Shunmay Yeung,Pratap Singhasivanon,Nicholas P. J. Day,Niklas Lindegardh,Duong Socheat,Nicholas J. White +22 more
TL;DR: The overall median clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours in Wang Pha (P<0.001) in each of the two locations as discussed by the authors.
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A molecular marker of artemisinin-resistant Plasmodium falciparum malaria
Frédéric Ariey,Benoit Witkowski,Chanaki Amaratunga,Johann Beghain,Anne-Claire Langlois,Nimol Khim,Saorin Kim,Valentine Duru,Christiane Bouchier,Laurence Ma,Pharath Lim,Rithea Leang,Socheat Duong,Sokunthea Sreng,Seila Suon,Char Meng Chuor,Denis Mey Bout,Sandie Menard,William O. Rogers,Blaise Genton,Thierry Fandeur,Olivo Miotto,Pascal Ringwald,Jacques Le Bras,Antoine Berry,Jean Christophe Barale,Rick M. Fairhurst,Françoise Benoit-Vical,Odile Mercereau-Puijalon,Didier Menard +29 more
TL;DR: Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance.
Journal ArticleDOI
Novel phenotypic assays for the detection of artemisinin- resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies
Benoit Witkowski,Chanaki Amaratunga,Nimol Khim,Sokunthea Sreng,Pheaktra Chim,Saorin Kim,Pharath Lim,Pharath Lim,Sivanna Mao,Chantha Sopha,Baramey Sam,Jennifer M. Anderson,Socheat Duong,Char Meng Chuor,Walter R. J. Taylor,Seila Suon,Odile Mercereau-Puijalon,Rick M. Fairhurst,Didier Menard +18 more
TL;DR: The in-vitro RSA of 0-3 h ring-stage parasites provides a platform for the molecular characterisation of artemisinin resistance and the ex-vivo RSA can be easily implemented where surveillance for artemis inin resistance is needed.
Journal ArticleDOI
Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study
Chanaki Amaratunga,Sokunthea Sreng,Seila Suon,Erika S. Phelps,Kasia Stepniewska,Pharath Lim,Chongjun Zhou,Sivanna Mao,Jennifer M. Anderson,Niklas Lindegardh,Hongying Jiang,Jianping Song,Xin-zhuan Su,Nicholas J. White,Arjen M. Dondorp,Tim J. Anderson,Michael P. Fay,Jianbing Mu,Socheat Duong,Rick M. Fairhurst +19 more
TL;DR: Heritable artemisinin resistance is established in a second Cambodian province and future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation.
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