Kremsner, PG

Krishna, S

Staines, HM

St George's Online Research Archive

Accepted Manuscript1 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. Artemisinin resistance and the blame-game  Sanjeev Krishna1,2,3, Henry M. Staines1, Peter G. Kremsner2,3 1Institute for Infection & Immunity, St George’s University of London, London, United Kingdom 2Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany 3Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon  Corresponding author: Prof Sanjeev Krishna, Institute for Infection & Immunity, St George’s University of London, Cranmer Terrace, Tooting, London Sw17 0RE, United Kingdom, Tel: +442087255836, Email: s.krishna@sgul.ac.uk  Alternate corresponding author: Prof Peter Kremsner, Institut für Tropenmedizin, Wilhelmstraße 27, 72074, Tübingen, Germany, Tel: +4970712982365, Email: peter.kremsner@uni-tuebingen.de     Clinical Infectious Diseases Advance Access published July 26, 2016 at St.George's Library on September 19, 2016http://cid.oxfordjournals.org/Downloaded from Accepted Manuscript2 Dear Editor,   Pyae Phyo and colleagues [1] conclude that the increasing prevalence of K13 mutations is the decisive factor for the declining efficacy of mefloquine-artesunate (MAS3) reported on the Thai-Myanmar border. They then make an unsupported assertion that the definition of “artemisinin resistance” by ourselves [2] may have contributed to a failure to contain artemisinin-based treatment failures in the greater Mekong area. This has put us firmly in the distinguished company of 2 other independent groups who also critically assessed the term ‘artemisinin resistance’ and with whom we shared similar conclusions [2-4].    After all, it was our collaborative efforts that first established the molecular marker of increased pfmdr1 copy number as being associated with treatment failures of artemisinin combination therapies (TFACT) [5]. Others confirmed our findings in different geographic areas (e.g. [6]). Some of our coauthors [5] at the time asserted without compunction that ‘artemisinin resistance’ would be unlikely to emerge in their lifetimes. They have not been accused of aiding the spread of parasites manifesting TFACT.   How have some later ideas in our opinion piece on ‘anti-dogmatic approaches to artemisinin resistance’ stood the test of time? We suggested that ‘increased gametocyte production’ may become ‘a marker of slow parasite clearance phenotype’ [2] and were gratified to see that some authors on Pyae Phyo’s paper went on to observe that ‘The higher proportions of pre-treatment and post-treatment gametocytemia in patients with slow parasite clearance suggest that artemisinin-resistance P. falciparum infections have a transmission advantage…’ [7] despite our opinion being unreferenced.    We also suggested that because conventional ACTs use incomplete courses of artemisinins ‘Contending that there is artemisinin resistance when cure of patients relies on the partner drug of an artemisinin is difficult to substantiate without additional studies’ [2]. Once again, our suggestions have been borne out by the important finding that kelch13 C508Y in Cambodia is associated with increased IC50 values to piperaquine in DHA-piperaquine treatments – focusing attention on the partner in the ACT and not only the artemisinin component [8]. The use of longer courses of ACT further supported our suggestion that artemisinins are  at St.George's Library on September 19, 2016http://cid.oxfordjournals.org/Downloaded from Accepted Manuscript3 conventionally underdosed [9], including findings made by the same individuals [7] who now criticise the very publication in which that suggestion was made.   Defining the precise nature of a problem such as multidrug resistant malaria provides the greatest service to those trying to deal with it. Critically examining terms such as ‘artemisinin resistance’ cannot stifle thinking about multidrug resistant parasites. In contrast, as we have illustrated it stimulates studies on resistant phenotypes rather than stimulating their geographic spread, particularly in light of the dispersed global distribution of kelch mutations [10].   To manage the problem of multidrug resistance we need new antimalarial classes and new diagnostics that can tell us about drug resistance status as well as confirming infection with malaria parasites. But to underpin these advances, we need to understand better both the mechanisms of action of artemisinins and how resistance to this class develops. These advances need inclusive debates rather than exclusive crusades.  Conflict of interests: The authors state no conflicts of interests References  1. Pyae Phyo A, Ashley EA, Anderson TJ, et al. Declining efficacy of artemisinin combination therapy against P. falciparum malaria on the Thai-Myanmar border (2003-2013): the role of parasite genetic factors. Clinical infectious diseases 2016 epub. 2. Krishna S, Kremsner PG. Antidogmatic approaches to artemisinin resistance: reappraisal as treatment failure with artemisinin combination therapy. Trends in parasitology 2013; 29(7): 313-7. 3. Ferreira PE, Culleton R, Gil JP, Meshnick SR. Artemisinin resistance in Plasmodium falciparum: what is it really? Trends in parasitology 2013; 29(7): 318-20. 4. Hastings IM, Kay K, Hodel EM. How robust are malaria parasite clearance rates as indicators of drug effectiveness and resistance? Antimicrobial agents and chemotherapy 2015; 59(10): 6428-36. 5. Price RN, Uhlemann AC, Brockman A, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 2004; 364(9432): 438-47.  at St.George's Library on September 19, 2016http://cid.oxfordjournals.org/Downloaded from Accepted Manuscript4 6. Ngalah BS, Ingasia LA, Cheruiyot AC, et al. Analysis of major genome loci underlying artemisinin resistance and pfmdr1 copy number in pre- and post-ACTs in western Kenya. Scientific reports 2015; 5: 8308. 7. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. The New England journal of medicine 2014; 371(5): 411-23. 8. Spring MD, Lin JT, Manning JE, et al. Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. The Lancet Infectious diseases 2015; 15(6): 683-91. 9. Saunders D, Khemawoot P, Vanachayangkul P, et al. Pharmacokinetics and pharmacodynamics of oral artesunate monotherapy in patients with uncomplicated Plasmodium falciparum malaria in western Cambodia. Antimicrobial agents and chemotherapy 2012; 56(11): 5484-93. 10. Menard D, Khim N, Beghain J, et al. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. The New England journal of medicine 2016; 374(25): 2453-64.   at St.George's Library on September 19, 2016http://cid.oxfordjournals.org/Downloaded from 

Artemisinin Resistance and the Blame Game.

Sanjeev Krishna

Henry M. Staines

Peter G. Kremsner

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Clinical Infectious Diseases

Artemisinin Resistance and the Blame Game

http://openaccess.sgul.ac.uk/108195/7/Clin%20Infect%20Dis%20%2D2016%2DKrishna%2Dcid_ciw501(2).pdf

Artemisinin Resistance and the Blame Game.

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