The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread

Charles J Woodrow, Nicholas J White, Charles J Woodrow, Nicholas J White

Abstract

Artemisinins are the most rapidly acting of currently available antimalarial drugs. Artesunate has become the treatment of choice for severe malaria, and artemisinin-based combination therapies (ACTs) are the foundation of modern falciparum malaria treatment globally. Their safety and tolerability profile is excellent. Unfortunately, Plasmodium falciparum infections with mutations in the 'K13' gene, with reduced ring-stage susceptibility to artemisinins, and slow parasite clearance in patients treated with ACTs, are now widespread in Southeast Asia. We review clinical efficacy data from the region (2000-2015) that provides strong evidence that the loss of first-line ACTs in western Cambodia, first artesunate-mefloquine and then DHA-piperaquine, can be attributed primarily to K13 mutated parasites. The ring-stage activity of artemisinins is therefore critical for the sustained efficacy of ACTs; once it is lost, rapid selection of partner drug resistance and ACT failure are inevitable consequences. Consensus methods for monitoring artemisinin resistance are now available. Despite increased investment in regional control activities, ACTs are failing across an expanding area of the Greater Mekong subregion. Although multiple K13 mutations have arisen independently, successful multidrug-resistant parasite genotypes are taking over and threaten to spread to India and Africa. Stronger containment efforts and new approaches to sustaining long-term efficacy of antimalarial regimens are needed to prevent a global malaria emergency.

Keywords: ACT; artemisinin; kelch; malaria; resistance; southeast Asia.

© FEMS 2016.

Figures

Graphical Abstract Figure.
Graphical Abstract Figure.
Artemisinin resistance in Plasmodium falciparum malaria is causing failure of artemisinin-based combination therapies across an expanding area of Southeast Asia, undermining control and elimination efforts. The potential global consequences can only be avoided by new approaches that ensure sustained efficacy for antimalarial regimens in malaria affected populations.
Figure 1.
Figure 1.
Longitudinal trends in cure rate (A), day 3 positivity (B) and K13 mutation prevalence (C), Cambodia, 2000–2015. In section A (cure rate), connecting lines are drawn for serial studies undertaken in Pursat (normal line), Pailin (dashed) and Oddar Meanchey (dotted) provinces. MAS = artesunate plus mefloquine, DP = DHA-piperaquine, Pyramax = artesunate-pyronaridine. Locations are stratified into western and eastern provinces according to their position with respect to the capital Phnom Penh, in line with previous work (Leang et al.2015). The midpoint of patient recruitment is used as the time point for each study, or half-way through the year if months were not stated. Only studies with n = 20 or more are included. For references see Additional File (Supporting Information).
Figure 2.
Figure 2.
Proposed mechanisms of artemisinin resistance. (A) Relevant biochemical pathways. In ring-stage parasites, artemisinin is primarily activated by haem produced in the process of haemoglobin digestion (1) although haem biosynthesis in mitochondria may also contribute (2). Activated artemisinins alkylate nearby proteins in an indiscriminate manner leading to cell death (3). In artemisinin-sensitive parasites, a transcriptional factor with potential to upregulate protein turnover and oxidative damage responses is bound via the K13 adaptor (4) leading to its ubiquitination and proteolysis (5). K13 mutation disrupts this binding (6) allowing the factor to enter the nucleus (7) with upregulation of a range of transcriptional responses that can mitigate the downstream consequences of artemisinins (8). (B) Proposed phenotypes associated with artemisinin resistance. The overall length and proportion of time spent in each stage appears relatively fixed in a given strain (A). By extending their ring-stage (B), parasites increase the period of reduced vulnerability to artemisinins. An alternative is to increase the proportion of parasites entering dormancy (C), a natural phenomenon observed in all parasite strains that allows escape from relatively short duration artemisinin exposures in patient treatments. Finally, increasing the proportion of parasites that differentiate into gametocytes (D) at a given timepoint could improve chances of transmission before treatment is administered.
Figure 3.
Figure 3.
The extent of ACT failure (in studies with at least 42 days of follow-up) and day 3 positivity across four time periods from 2000 to the present. If two studies were available in one location for the same time period, the higher failure rate is shown. MAS3: artesunate plus mefloquine; DP: DHA-piperaquine. For references, see Additional File (Supporting Information).
Figure 4.
Figure 4.
The relationship between the proportion of parasites with K13 propeller mutations and day 3 positivity in clinical studies in Southeast Asia. The oval ring indicates data from Yunnan Province, China in which the F446I K13 mutation was the most common. Only studies with n = 20 or more are included. For references see Additional File (Supporting Information).

References

    1. Adjuik M, Babiker A, Garner P et al. , Artesunate combinations for treatment of malaria: meta-analysis, Lancet, 2004, 363, 9, 17
    1. Alin MH, Bjorkman A, Concentration and time dependency of artemisinin efficacy against Plasmodium falciparum in vitro, Am J Trop Med Hyg, 1994, 50, 771, 6
    1. Alker AP, Lim P, Sem R et al. , Pfmdr1 and in vivo resistance to artesunate-mefloquine in falciparum malaria on the Cambodian-Thai border, Am J Trop Med Hyg, 2007, 76, 641, 7
    1. Amaratunga C, Lim P, Suon S et al. , Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study, Lancet Infect Dis, 2016, 16, 357, 65
    1. Amaratunga C, Neal AT, Fairhurst RM, Flow cytometry-based analysis of artemisinin-resistant Plasmodium falciparum in the ring-stage survival assay, Antimicrob Agents Ch, 2014, 58, 4938, 40
    1. Amaratunga C, Sreng S, Suon S et al. , Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study, Lancet Infect Dis, 2012, 12, 851, 8
    1. Anderson TJ, Nair S, Nkhoma S et al. , High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia, J Infect Dis, 2010, 201, 1326, 30
    1. Ariey F, Witkowski B, Amaratunga C et al. , A molecular marker of artemisinin-resistant Plasmodium falciparum malaria, Nature, 2014, 505, 50, 5
    1. Ashley EA, Dhorda M, Fairhurst RM et al. , Spread of artemisinin resistance in Plasmodium falciparum malaria, N Engl J Med, 2014, 371, 411, 23
    1. Bancone G, Chowwiwat N, Somsakchaicharoen R et al. , Single low dose primaquine (0.25 mg/kg) does not cause clinically significant haemolysis in G6PD deficient subjects, PLoS One, 2016, 11, e0151898.
    1. Basco LK. Field Application of In Vitro Assays for the Sensitivity of Human Malaria Parasites to Antimalarial Drugs, Geneva, WHO, 2007
    1. Bethell D, Se Y, Lon C et al. , Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial, PLoS One, 2011, 6, e19283.
    1. Bhatt S, Weiss DJ, Cameron E et al. , The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015, Nature, 2015, 526, 207, 11
    1. Boni MF, White NJ, Baird JK, The community as the patient in malaria-endemic areas: preempting drug resistance with multiple first-line therapies, PLoS Med, 2016, 13, e1001984.
    1. Borrmann S, Sasi P, Mwai L et al. , Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast, PLoS One, 2011, 6, e26005.
    1. Boyden LM, Choi M, Choate KA et al. , Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities, Nature, 2012, 482, 98, 102
    1. Buffet PA, Milon G, Brousse V et al. , Ex vivo perfusion of human spleens maintains clearing and processing functions, Blood, 2006, 107, 3745, 52
    1. Carrara VI, Lwin KM, Phyo AP et al. , Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai-Myanmar border, 1999–2011: an observational study, PLoS Med, 2013, 10, e1001398.
    1. Carrara VI, Zwang J, Ashley EA et al. , Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment, PLoS One, 2009, 4, e4551.
    1. Cheeseman IH, Miller BA, Nair S et al. , A major genome region underlying artemisinin resistance in malaria, Science, 2012, 336, 79, 82
    1. Chenet SM, Akinyi Okoth S, Huber CS et al. , Independent emergence of the Plasmodium falciparum kelch propeller domain mutant allele C580Y in Guyana, J Infect Dis, 2016, 213, 1472, 5
    1. Chotivanich K, Tripura R, Das D et al. , Laboratory detection of artemisinin-resistant Plasmodium falciparum, Antimicrob Agents Ch, 2014, 58, 3157, 61
    1. Chotivanich K, Udomsangpetch R, Dondorp A et al. , The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria, J Infect Dis, 2000, 182, 629, 33
    1. Cobbold SA, Chua HH, Nijagal B et al. , Metabolic dysregulation induced in Plasmodium falciparum by dihydroartemisinin and other front-line antimalarial drugs, J Infect Dis, 2016, 213, 276, 86
    1. Curtis CF, Otoo LN, A simple model of the build-up of resistance to mixtures of anti-malarial drugs, T Roy Soc Trop Med H, 1986, 80, 889, 92
    1. Das D, Tripura R, Phyo AP et al. , Effect of high-dose or split-dose artesunate on parasite clearance in artemisinin-resistant falciparum malaria, Clin Infect Dis, 2013, 56, e48, 58
    1. David-Bosne S, Clausen MV, Poulsen H et al. , Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes, Nat Struct Mol Biol, 2016, 23, 1, 2
    1. Denis MB, Davis TM, Hewitt S et al. , Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria, Clin Infect Dis, 2002, 35, 1469, 76
    1. Denis MB, Tsuyuoka R, Lim P et al. , Efficacy of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia, Trop Med Int Health, 2006a, 11, 1800, 7
    1. Denis MB, Tsuyuoka R, Poravuth Y et al. , Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia, Trop Med Int Health, 2006b, 11, 1360, 6
    1. Dogovski C, Xie SC, Burgio G et al. , Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance, PLoS Biol, 2015, 13, e1002132.
    1. Dondorp A, Nosten F, Stepniewska K et al. , Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial, Lancet, 2005, 366, 717, 25
    1. Dondorp AM, Fanello CI, Hendriksen IC et al. , Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial, Lancet, 2010, 376, 1647, 57
    1. Dondorp AM, Nosten F, Yi P et al. , Artemisinin resistance in Plasmodium falciparum malaria, N Engl J Med, 2009, 361, 455, 67
    1. Duru V, Khim N, Leang R et al. , Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations, BMC Med, 2015, 13, 305.
    1. Fairhurst RM., Understanding artemisinin-resistant malaria: what a difference a year makes, Curr Opin Infect Dis, 2015, 28, 417, 25
    1. Fairhurst RM, Nayyar GM, Breman JG et al. , Artemisinin-resistant malaria: research challenges, opportunities, and public health implications, Am J Trop Med Hyg, 2012, 87, 231, 41
    1. Flegg JA, Guerin PJ, Nosten F et al. , Optimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivatives, Malaria J, 2013, 12, 411
    1. Flegg JA, Guerin PJ, White NJ et al. , Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator, Malaria J, 2011, 10, 339
    1. Gardner KB, Sinha I, Bustamante LY et al. , Protein-based signatures of functional evolution in Plasmodium falciparum, BMC Evol Biol, 2011, 11, 257.
    1. Geary TG, Divo AA, Jensen JB, Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture, Am J Trop Med Hyg, 1989, 40, 240, 4
    1. Ghorbal M, Gorman M, Macpherson CR et al. , Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system, Nat Biotechnol, 2014, 32, 819, 21
    1. Hayes JD, McMahon M, The double-edged sword of Nrf2: subversion of redox homeostasis during the evolution of cancer, Mol Cell, 2006, 21, 732, 4
    1. Hien TT, Thuy-Nhien NT, Phu NH. et al. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam, Malaria J, 2012, 11, 355
    1. Hott A, Casandra D, Sparks KN, Morton LC et al. , Artemisinin-resistant Plasmodium falciparum parasites exhibit altered patterns of development in infected erythrocytes, Antimicrob Agents Ch, 2015, 59, 3156, 67
    1. Huang F, Takala-Harrison S, Jacob CG et al. , A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment, J Infect Dis, 2015, 212, 1629, 35
    1. Imwong M, Jindakhad T, Kunasol C et al. , An outbreak of artemisinin resistant falciparum malaria in Eastern Thailand, Sci Rep, 2015, 5, 17412.
    1. Ismail HM, Barton V, Phanchana M et al. , Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7, P Natl Acad Sci USA, 2016, 113, 2080, 5
    1. Janssens B, van Herp M, Goubert L et al. , A randomized open study to assess the efficacy and tolerability of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia, Trop Med Int Health, 2007, 12, 251, 9
    1. Kamau E, Campino S, Amenga-Etego L et al. , K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa, J Infect Dis, 2015, 211, 1352, 5
    1. Khin HS, Chen I, White C et al. , Availability and quality of anti-malarials among private sector outlets in Myanmar in 2012: results from a large, community-based, cross-sectional survey before a large-scale intervention, Malaria J, 2015, 14, 269
    1. Klonis N, Crespo-Ortiz MP, Bottova I et al. , Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion, P Natl Acad Sci USA, 2011, 108, 11405, 10
    1. Klonis N, Xie SC, McCaw JM et al. , Altered temporal response of malaria parasites determines differential sensitivity to artemisinin, P Natl Acad Sci USA, 2013, 110, 5157, 62
    1. Kyaw MP, Nyunt MH, Chit K et al. , Reduced susceptibility of Plasmodium falciparum to artesunate in southern Myanmar, PLoS One, 2013, 8, e57689.
    1. Leang R, Barrette A, Bouth DM et al. , Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010, Antimicrob Agents Ch, 2013, 57, 818, 26
    1. Leang R, Canavati SE, Khim N et al. , Efficacy and safety of pyronaridine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in western Cambodia, Antimicrob Agents Ch, 2016, 60, 3884, 90
    1. Leang R, Taylor WR, Bouth DM et al. , Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in Western Cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment, Antimicrob Agents Ch, 2015, 59, 4719, 26
    1. Li GQ, Arnold K, Guo XB et al. , Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria, Lancet, 1984, 2, 1360, 1
    1. Lon C, Manning JE, Vanachayangkul P et al. , Efficacy of two versus three-day regimens of dihydroartemisinin-piperaquine for uncomplicated malaria in military personnel in northern Cambodia: an open-label randomized trial, PLoS One, 2014, 9, e93138.
    1. Maiga-Ascofare O, May J, Is the A578S single-nucleotide polymorphism in K13-propeller a marker of emerging resistance to artemisinin among plasmodium falciparum in Africa?, J Infect Dis, 2016, 213, 165, 6
    1. MalariaGEN Plasmodium falciparum Community Project , Genomic epidemiology of artemisinin resistant malaria, Elife, 2016, 5
    1. Maude RJ, Pontavornpinyo W, Saralamba S et al. , The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia, Malaria J, 2009, 8, 31
    1. Mbengue A, Bhattacharjee S, Pandharkar T et al. , A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria, Nature, 2015, 520, 683, 7
    1. Menard D, Khim N, Beghain J et al. , A worldwide map of Plasmodium falciparum K13-propeller polymorphisms, N Engl J Med, 2016, 374, 2453, 64
    1. Menard S, Ben Haddou T, Ramadani AP et al. , Induction of multidrug tolerance in Plasmodium falciparum by extended artemisinin pressure, Emerg Infect Dis, 2015, 21, 1733, 41
    1. Miao M, Wang Z, Yang Z et al. , Genetic diversity and lack of artemisinin selection signature on the Plasmodium falciparum ATP6 in the Greater Mekong Subregion, PLoS One, 2013, 8, e59192.
    1. Miotto O, Almagro-Garcia J, Manske M et al. , Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia, Nat Genet, 2013, 45, 648, 55
    1. Miotto O, Amato R, Ashley EA et al. , Genetic architecture of artemisinin-resistant Plasmodium falciparum, Nat Genet, 2015, 47, 226, 34
    1. Mok S, Ashley EA, Ferreira PE et al. , Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance, Science, 2015, 347, 431, 5
    1. Na-Bangchang K, Ruengweerayut R, Mahamad P et al. , Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border, Malar J, 2010, 9, 273.
    1. Nayyar GM, Breman JG, Newton PN et al. , Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa, Lancet Infect Dis, 2012, 12, 488, 96
    1. Newton P, Proux S, Green M et al. , Fake artesunate in southeast Asia, Lancet, 2001, 357, 1948, 50
    1. Nguyen TD, Olliaro P, Dondorp AM et al. , Optimum population-level use of artemisinin combination therapies: a modelling study, Lancet Glob Health, 2015, 3, e758, 66
    1. Noedl H, Se Y, Schaecher K et al. , Evidence of artemisinin-resistant malaria in western Cambodia, N Engl J Med, 2008, 359, 2619, 20
    1. Noedl H, Se Y, Sriwichai S et al. , Artemisinin resistance in Cambodia: a clinical trial designed to address an emerging problem in Southeast Asia, Clin Infect Dis, 2010, 51, e82, 89
    1. Nosten F, Luxemburger C, ter Kuile FO et al. , Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination, J Infect Dis, 1994, 170, 971, 7
    1. Nosten F, van Vugt M, Price R et al. , Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study, Lancet, 2000, 356, 297, 302
    1. Nyunt MH, Hlaing T, Oo HW et al. , Molecular assessment of artemisinin resistance markers, polymorphisms in the K13 propeller, and a multidrug-resistance gene in the Eastern and Western Border Areas of Myanmar, Clin Infect Dis, 2015, 60, 1208, 15
    1. Ouattara A, Kone A, Adams M et al. , Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali, Am J Trop Med Hyg, 2015, 92, 1202, 6
    1. Padmanabhan B, Tong KI, Ohta T et al. , Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer, Mol Cell, 2006, 21, 689, 700
    1. Peak CM, Thuan PD, Britton A et al. , Measuring the association between artemisinin-based case management and malaria incidence in southern Vietnam, 1991–2010, Am J Trop Med Hyg, 2015, 92, 811, 7
    1. Pennings PS, Hermisson J, Soft sweeps III: the signature of positive selection from recurrent mutation, PLoS Genet, 2006, 2, e186.
    1. Phyo AP, 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, Clin Infect Dis, 2016a
    1. Phyo AP, Jittamala P, Nosten FH et al. , Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial, Lancet Infect Dis, 2016b, 16, 61, 9
    1. Phyo AP, Nkhoma S, Stepniewska K et al. , Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study, Lancet, 2012, 379, 1960, 6
    1. Price R, Luxemburger C, van Vugt M et al. , Artesunate and mefloquine in the treatment of uncomplicated multidrug-resistant hyperparasitaemic falciparum malaria, T Roy Soc Trop Med H, 1998a, 92, 207, 11
    1. Price R, van Vugt M, Nosten F et al. , Artesunate versus artemether for the treatment of recrudescent multidrug-resistant falciparum malaria, Am J Trop Med Hyg, 1998b, 59, 883, 8
    1. Price RN, Uhlemann AC, Brockman A et al. , Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number, Lancet, 2004, 364, 438, 47
    1. Putaporntip C, Kuamsab N, Kosuwin R et al. , Natural selection of K13 mutants of Plasmodium falciparum in response to artemisinin combination therapies in Thailand, Clin Microbiol Infect, 2016, 22, 285, e281, 8
    1. Rogers WO, Sem R, Tero T et al. , Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia, Malaria J, 2009, 8, 10
    1. Rogerson SJ, Wijesinghe RS, Meshnick SR, Host immunity as a determinant of treatment outcome in Plasmodium falciparum malaria, Lancet Infect Dis, 2010, 10, 51, 9
    1. Roper C, Alifrangis M, Ariey F et al. , Molecular surveillance for artemisinin resistance in Africa, Lancet Infect Dis, 2014, 14, 668, 70
    1. Roper C, Pearce R, Nair S et al. , Intercontinental spread of pyrimethamine-resistant malaria, Science, 2004, 305, 1124.
    1. Rottmann M, McNamara C, Yeung BK et al. , Spiroindolones, a potent compound class for the treatment of malaria, Science, 2010, 329, 1175, 80
    1. Rueangweerayut R, Phyo AP, Uthaisin C et al. , Pyronaridine-artesunate versus mefloquine plus artesunate for malaria, N Engl J Med, 2012, 366, 1298, 309
    1. Saralamba S, Pan-Ngum W, Maude RJ et al. , Intrahost modeling of artemisinin resistance in Plasmodium falciparum, P Natl Acad Sci USA, 2011, 108, 397, 402
    1. Satimai W, Sudathip P, Vijaykadga S et al. , Artemisinin resistance containment project in Thailand. II: Responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia, Malaria J, 2012, 11, 300
    1. Saunders DL, Vanachayangkul P, Lon C, Dihydroartemisinin-piperaquine failure in Cambodia, N Engl J Med, 2014, 371, 484, 5
    1. Shute PG, Maryon M, A contribution to the problem of strains of human plasmodium, Riv Malariol, 1954, 33, 1, 21
    1. Simpson JA, McCaw J, Fowkes FJ, Parasite strain, host immunity, and circulating blood cells with dead parasites: why predicting malaria parasite clearance is not a simple task, Antimicrob Agents Ch, 2016, 60, 1172
    1. Skinner TS, Manning LS, Johnston WA et al. , In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs, Int J Parasitol, 1996, 26, 519, 25
    1. Smithuis F, Kyaw MK, Phe O et al. , Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial, Lancet Infect Dis, 2010, 10, 673, 81
    1. 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, Lancet Infect Dis, 2015, 15, 683, 91
    1. St Laurent B, Miller B, Burton TA et al. , Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa, Nat Commun, 2015, 6, 8614.
    1. Stepniewska K, Ashley E, Lee SJ et al. , In vivo parasitological measures of artemisinin susceptibility, J Infect Dis, 2010, 201, 570, 9
    1. Straimer J, Gnadig NF, Witkowski B et al. , K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates, Science, 2015, 347, 428, 31
    1. Takala-Harrison S, Clark TG, Jacob CG et al. , Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia, P Natl Acad Sci USA, 2013, 110, 240, 5
    1. Takala-Harrison S, Jacob CG, Arze C et al. , Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia, J Infect Dis, 2015, 211, 670, 9
    1. Talundzic E, Okoth SA, Congpuong K et al. , Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign, PLoS Pathog, 2015, 11, e1004789.
    1. Taylor SM, Parobek CM, DeConti DK et al. , Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study, J Infect Dis, 2015, 211, 680, 8
    1. ter Kuile F, White NJ, Holloway P et al. , Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria, Exp Parasitol, 1993, 76, 85, 95
    1. Teuscher F, Gatton ML, Chen N et al. , Artemisinin-induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure, J Infect Dis, 2010, 202, 1362, 8
    1. Thriemer K, Hong NV, Rosanas-Urgell A et al. , Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam, Antimicrob Agents Ch, 2014, 58, 7049, 55
    1. Tilley L, Straimer J, Gnadig NF et al. , Artemisinin action and resistance in Plasmodium falciparum, Trends Parasitol, 2016
    1. Toure OA, Rulisa S, Anvikar AR et al. , Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study, Malaria J, 2015, 14, 469
    1. Toure OA, Valecha N, Tshefu AK et al. , A Phase 3, Double-blind, randomized study of arterolane maleate-piperaquine phosphate vs artemether-lumefantrine for falciparum malaria in adolescent and adult patients in Asia and Africa, Clin Infect Dis, 2016, 62, 964, 71
    1. Tun KM, Imwong M, Lwin KM et al. , Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker, Lancet Infect Dis, 2015, 15, 415, 21
    1. Tun KM, Jeeyapant A, Imwong M et al. , Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study, Malaria J, 2016, 15, 185
    1. Tyner SD, Lon C, Se Y et al. , Ex vivo drug sensitivity profiles of Plasmodium falciparum field isolates from Cambodia and Thailand, 2005 to 2010, determined by a histidine-rich protein-2 assay, Malaria J, 2012, 11, 198
    1. Venkatesan M, Gadalla NB, Stepniewska K et al. , Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine, Am J Trop Med Hyg, 2014, 91, 833, 43
    1. Vijaykadga S, Rojanawatsirivej C, Cholpol S et al. , In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003, Trop Med Int Health, 2006, 11, 211, 9
    1. Wang J, Zhang CJ, Chia WN et al. , Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum, Nat Commun, 2015a, 6, 10111.
    1. Wang Z, Wang Y, Cabrera M et al. , Artemisinin resistance at the China-Myanmar border and association with mutations in the K13 propeller gene, Antimicrob Agents Ch, 2015b, 59, 6952, 9
    1. Wells TN, Hooft van Huijsduijnen R, Van Voorhis WC, Malaria medicines: a glass half full?, Nat Rev Drug Discov, 2015, 14, 424, 42
    1. White LJ, Flegg JA, Phyo AP et al. , Defining the in vivo phenotype of artemisinin-resistant falciparum malaria: a modelling approach, PLoS Med, 2015, 12, e1001823.
    1. White NJ., Antimalarial drug resistance, J Clin Invest, 2004, 113, 1084, 92
    1. White NJ, Pongtavornpinyo W, Maude RJ et al. , Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance, Malaria J, 2009, 8, 253
    1. White NJ, Pukrittayakamee S, Phyo AP et al. , Spiroindolone KAE609 for falciparum and vivax malaria, N Engl J Med, 2014, 371, 403, 10
    1. Win AA, Imwong M, Kyaw MP et al. , K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar, Malaria J, 2016, 15, 110
    1. Winzeler EA, Manary MJ, Drug resistance genomics of the antimalarial drug artemisinin, Genome Biol, 2014, 15, 544.
    1. Witkowski B, Amaratunga C, Khim N et al. , Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies, Lancet Infect Dis, 2013a, 13, 1043, 9
    1. Witkowski B, Khim N, Chim P et al. , Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia, Antimicrob Agents Ch, 2013b, 57, 914, 23
    1. Witkowski B, Lelievre J, Barragan MJ et al. , Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism, Antimicrob Agents Ch, 2010, 54, 1872, 7
    1. World Health Organization , Chemotherapy of Malaria. Report of a WHO scientific group. (WHO Technical Report Series, No. 375), Geneva, Switzerland, World Health Organization, 1967
    1. World Health Organization , Status Report on Artemisinin Resistance: September 2015, Geneva, Switzerland, World Health Organization, 2015
    1. WWARN ACT Africa Baseline Study Group , 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 Med, 2015, 13, 212.
    1. WWARN Artemether-Lumefantrine Dose Impact Study Group , The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data, Lancet Infect Dis, 2015, 15, 692, 702
    1. WWARN Artesunate-Amodiaquine Study Group , The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data, BMC Med, 2015, 13, 66.
    1. WWARN DHA-Piperaquine Study Group , The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data, PLoS Med, 2013, 10, e1001564, discussion e1001564
    1. WWARN Lumefantrine PK-PD Study Group , Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data, BMC Med, 2015, 13, 227.
    1. WWARN Parasite Clearance Study Group , Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis, Malaria J, 2015, 14, 359
    1. Xie SC, Dogovski C, Hanssen E et al. , Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins, J Cell Sci, 2016, 129, 406, 16
    1. Ye R, Hu D, Zhang Y et al. , Distinctive origin of artemisinin-resistant Plasmodium falciparum on the China-Myanmar border, Sci Rep, 2016, 6, 20100.
    1. Yeung S, Van Damme W, Socheat D et al. , Access to artemisinin combination therapy for malaria in remote areas of Cambodia, Malar J, 2008, 7, 96.

Source: PubMed

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