Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses\na major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to\nartemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African\ncountries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs).\nMethods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials\n(uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa,\nbetween 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial\nResistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological\nresponse were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in\nincluded studies was evaluated based on study design, methodology and missing data.\nResults: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine\n(n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite\nclearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5ââ?¬â??64.9) on day 1 to 6.7 %\n(95 % CI: 4.8ââ?¬â??8.7) on day 2 and 0.9 % (95 % CI: 0.5ââ?¬â??1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %.\nIndependent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16\n(95 % CI: 1.08ââ?¬â??1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 Ã?°C) (AOR = 1.50 (95 % CI: 1.06ââ?¬â??2.13),\nP = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21ââ?¬â??3.44), P = 0.008); areas of low/moderate transmission setting\n(AOR = 2.71 (95 % CI: 1.38ââ?¬â??5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine\n(AOR = 2.27 (95 % CI: 1.14ââ?¬â??4.51), P = 0.020, compared to dihydroartemisinin-piperaquine).\nConclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across\nthe sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50\npatients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold\nof 10 % to trigger further investigation of artemisinin susceptibility.
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