by The Worldwide Antimalarial Resistance Network (WWARN) Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group – includes Kiechel JR as co-author. BioMed Central Medicine, 2015, 13:212 DOI 10.1186/s12916-015-0445-x

Summary: 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. The three ACTs assessed in this analysis – artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine – 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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by The Worldwide Antimalarial Resistance Network (WWARN) AS-AQ Study Group including Diap G, Kiechel JR, Sharma B. BMC Medicine 2015, doi: 10.1186/s12916-015-0301-z.

Summary: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. The impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria was investigated using pooled patient data by the  Worldwide Antimalarial Resistance Network (WWARN). There was substantial variation in the total dose of amodiaquine administered in different ASAQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

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by Poyer S, Shewchuk T, Tougher S, Ye Y; ACTwatch Group, Mann AG, Willey BA, Thomson R, Amuasi JH, Ren R, Wamukoya M, Taylor M, Nguah SB, Mberu B, Kalolella A, Juma E, Festo C, Johanes B, Diap G, Bruxvoort K, Ansong D, Hanson K, Arnold F, Goodman C. Tropical Medicine & International Health 2015, doi: 10.1111/tmi.12491.

Summary: The aim of this study was to describe the state of the public and private malaria diagnostics market shortly after WHO updated its guidelines for testing all suspected malaria cases prior to treatment. Eighteen months after WHO updated its case management guidelines, RDT (rapid diagnostic test) availability remained poor in the private sector in sub-Saharan Africa. Given the ongoing importance of the private sector as a source of fever treatment, the goal of universal diagnosis will not be achievable under current circumstances. These results constitute national baselines against which progress in scaling-up diagnostic tests can be assessed.

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by Ogutu B, Juma E, Obonyo C, Jullien V, Carn G, Vaillant M, Taylor WRJ, Kiechel JR. Malaria Journal 2014, doi:10.1186/1475-2875-13-498.

Summary: As part of the development of a fixed dose combination of ASAQ, a pharmacokinetic (PK) and safety study was performed comparing the fixed and loose combinations to complement existing population PK data and explore PK and pharmacodynamic relationships. Tolerability of both formulations was good. For QTcB, a parameter for ECG modifications, increases were modest and due to rising DAQ concentrations and falling heart rates as malaria resolved. Rapid parasite clearance rates and no resistant infections suggest effective pharmacokinetics of both formulations.

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by Venkatesan M, Gadalla NB, Stepniewska K, Dahal P, Nsanzabana C, Moriera C, Price RN, Mårtensson A, Rosenthal PJ, Dorsey G, Sutherland CJ, Guérin P, Davis TME, Ménard D, Adam I, Ademowo G, Arze C, Baliraine FN, Berens-Riha N, Björkman A, Borrmann S, Checchi F, Desai M, Dhorda M, Djimdé AA, El-Sayed BB, Eshetu T, Eyase F, Falade C, Faucher JF, Fröberg G, Grivoyannis A, Hamour S, Houzé S, Johnson J, Kamugisha E, Kariuki S, Kiechel JR, Kironde F, Kofoed PE, LeBras J, Malmberg M, Mwai L, Ngasala B, Nosten F, Nsobya SL, Nzila A, Oguike M, Dahlström Otienoburu S, Ogutu B, Ouédraogo JB, Piola P, Rombo L, Schramm B, Somé AF, Thwing J, Ursing J, Wong RPM, Zeynudin A, Zongo I, Plowe CV, Hopkins Sibley C. The American Journal of Tropical Medicine and Hygiene 2014, doi:10.4269/ajtmh.14-0031.

Summary: Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug.  Some resistance genes have been found to be associated with decreased sensitivity to amodiaquine and lumefantrine, but effects on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

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by Zwang J, Dorsey G, Mårtensson A, d’Alessandro U, Ndiaye JL, Karema C, Djimde A, Brasseur P, Sirima SB, Olliaro P. Malaria Journal 2014, doi:10.1186/1475-2875-13-114.

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by Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, Pinoges L, Sundaygar T, Zolia YM, Jones JJ, Comte E, Bruneel A, Branger M, Jullien V, Carn G, Kiechel JR, Ashley EA and Guérin PJ, Malaria Journal, July 2013.

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by Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, Pinoges L, Sundaygar T, Zolia YM, Jones JJ, Comte E, Bruneel A, Branger M, Jullien V, Carn G, Kiechel J, Ashley EA, and Guérin PJ, Malaria Journal, July 2013.

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by Amuasi JH, Diap G, Blay Nguah S, Karikari P, Boakye I, Jambai A, Kumba Lahai W, Louie KS, Kiechel JR. PLoS one, October 2012.

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by Zwang J, Dorsey G, Djimdé A, Karema C, Mårtensson A, Ndiaye JL, Sirima SB, Olliaro P. Malar J. Malaria Journal 2012, DOI: 10.1186/1475-2875-11-260

Summary: Of the 6,179 patients enrolled in the study, 50% received ASAQ, 20% another ACT, and 30% a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments.

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