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BMC Med. 2015 Sep 7;13:212. doi: 10.1186/s12916-015-0445-x.

Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

Collaborators (152)

Abdulla S, Adam I, Adjei GO, Adjuik MA, Alemayehu B, Allan R, Arinaitwe E, Ashley EA, Ba MS, Barennes H, Barnes KI, Bassat Q, Baudin E, Berens-Riha N, Björkman A, Bompart F, Bonnet M, Borrmann S, Bousema T, Brasseur P, Bukirwa H, Checchi F, Dahal P, D'Alessandro U, Desai M, Dicko A, Djimdé AA, Dorsey G, Doumbo OK, Drakeley CJ, Duparc S, Eshetu T, Espié E, Etard JF, Faiz AM, Falade CO, Fanello CI, Faucher JF, Faye B, Faye O, Filler S, Flegg JA, Fofana B, Fogg C, Gadalla NB, Gaye O, Genton B, Gething PW, Gil JP, González R, Grandesso F, Greenhouse B, Greenwood B, Grivoyannis A, Guerin PJ, Guthmann JP, Hamed K, Hamour S, Hay SI, Hodel EM, Humphreys GS, Hwang J, Ibrahim ML, Jima D, Jones JJ, Jullien V, Juma E, Kachur PS, Kager PA, Kamugisha E, Kamya MR, Karema C, Kayentao K, Kiechel JR, Kironde F, Kofoed PE, Kremsner PG, Krishna S, Lameyre V, Lell B, Lima A, Makanga M, Malik EM, Marsh K, Mårtensson A, Massougbodji A, Menan H, Menard D, Menéndez C, Mens PF, Meremikwu M, Moreira C, Nabasumba C, Nambozi M, Ndiaye JL, Ngasala BE, Nikiema F, Nsanzabana C, Ntoumi F, Oguike M, Ogutu BR, Olliaro P, Omar SA, Ouédraogo JB, Owusu-Agyei S, Penali LK, Pene M, Peshu J, Piola P, Plowe CV, Premji Z, Price RN, Randrianarivelojosia M, Rombo L, Roper C, Rosenthal PJ, Sagara I, Same-Ekobo A, Sawa P, Schallig HD, Schramm B, Seck A, Shekalaghe SA, Sibley CH, Sinou V, Sirima SB, Somé FA, Sow D, Staedke SG, Stepniewska K, Sutherland CJ, Swarthout TD, Sylla K, Talisuna AO, Taylor WR, Temu EA, Thwing JI, Tine RC, Tinto H, Tommasini S, Touré OA, Ursing J, Vaillant MT, Valentini G, Van den Broek I, Van Vugt M, Ward SA, Winstanley PA, Yavo W, Yeka A, Zolia YM, Zongo I.

Author information

WorldWide Antimalarial Resistance Network (WWARN); Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, UK.



Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).


A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data.


In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).


The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

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