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

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; Bjorkman, A; Bompart, F; Bonnet, M; Borrmann, S; Bousema, T; Brasseur, P; Bukirwa, H; Checchi, F; Dahal, P; D'Alessandro, U; Desai, M; Dicko, A; Djimde, AA; Dorsey, G; Doumbo, OK; Drakeley, CJ; Duparc, S; Eshetu, T; Espie, 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; Gonzalez, 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; Martensson, A; Massougbodji, A; Menan, H; Menard, D; Menendez, 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; Ouedraogo, 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, H; Schramm, B; Seck, A; Shekalaghe, SA; Sibley, CH; Sinou, V; Sirima, SB; Som, FA; Sow, D; Staedke, SG; Stepniewska, K; Sutherland, CJ; Swarthout, TD; Sylla, K; Talisuna, AO; Taylor, WRJ; Temu, EA; Thwing, JI; Tine, RCK; Tinto, H; Tommasini, S; Toure, 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; Based, WA; (2015) 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. BMC medicine, 13. ISSN 1741-7015 DOI:

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Background: 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). Methods: 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. Results: 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 degrees 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). Conclusions: 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.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Disease Control
Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Research Centre: Malaria Centre
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PubMed ID: 26343145
Web of Science ID: 360804700001


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