Triple Artemisinin-Based Combination Therapies for Malaria – A New Paradigm?

Abstract

Artemisinin and partner drug resistance have resulted in high failure rates of artemisinin-based combination therapies (ACTs) in the GMS. Spread or emergence of resistance beyond the GMS are threats to malaria control.Triple ACTs (TACTs), combining an artemisinin and two existing partner drugs, could be a stop-gap therapy for treating multidrug-resistant malaria until new antimalarials are available. Where resistance is not established, deployment of TACTs could delay or prevent emergence of resistance and could prolong the longevity of antimalarial compounds used in any triple-drug combination.TACTs must be safe, well-tolerated, effective, and affordable. Fixed-dose combinations of three drugs in the same tablet will likely improve adherence. Barriers that hinder deployment and adherence must be identified and addressed early in the development of TACTs. Recent gains in the fight against malaria are threatened by the emergence and spread of artemisinin and partner drug resistance in Plasmodium falciparum in the Greater Mekong Subregion (GMS). When artemisinins are combined with a single partner drug, all recommended artemisinin-based combination therapies have shown reduced efficacy in some countries in the GMS at some point. Novel drugs are not available for the near future. Triple artemisinin-based combination therapies, combining artemisinins with two currently available partner drugs, will provide one of the last remaining safe and effective treatments for falciparum malaria that can be deployed rapidly in the GMS, whereas their deployment beyond the GMS could delay or prevent the global emergence and spread of resistance to currently available drugs. Recent gains in the fight against malaria are threatened by the emergence and spread of artemisinin and partner drug resistance in Plasmodium falciparum in the Greater Mekong Subregion (GMS). When artemisinins are combined with a single partner drug, all recommended artemisinin-based combination therapies have shown reduced efficacy in some countries in the GMS at some point. Novel drugs are not available for the near future. Triple artemisinin-based combination therapies, combining artemisinins with two currently available partner drugs, will provide one of the last remaining safe and effective treatments for falciparum malaria that can be deployed rapidly in the GMS, whereas their deployment beyond the GMS could delay or prevent the global emergence and spread of resistance to currently available drugs. Artemisinins are the most potent antimalarial drugs available to date, with a 10 000-fold reduction in Plasmodium falciparum parasite burden per 48 h asexual parasite life cycle period in infections caused by artemisinin-sensitive parasites [1.Dondorp A.M. et al.Artemisinin resistance in Plasmodium falciparum malaria.N. Engl. J. Med. 2009; 361: 455-467Crossref PubMed Scopus (2339) Google Scholar]. Artemisinins have a short elimination half-life (see Glossary) of ~1 h, which then requires a longer regimen for complete elimination of the infection, but also shortens the window of selection in which drug-resistant parasites outgrow drug-sensitive parasites [2.Meshnick S.R. et al.Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy.Microbiol. Rev. 1996; 60: 301-315Crossref PubMed Google Scholar,3.Okell L.C. et al.Modelling the impact of artemisinin combination therapy and long-acting treatments on malaria transmission intensity.PLoS Med. 2008; 5 (discussion e226)e226Crossref PubMed Scopus (105) Google Scholar]. As early as 1984, Li et al. recognised that, even with 3 days of high-dose artemisinin treatment, ~40% of patients will come back with recrudescent infections [4.Li G.Q. et al.Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria.Lancet. 1984; 2: 1360-1361Abstract PubMed Scopus (94) Google Scholar]. Due to the short half-life of artemisinin, and probably also due to artemisinin-induced dormancy in asexual-stage parasites, even 7 days of monotherapy is not completely effective [5.Li G.Q. et al.Clinical trials of artemisinin and its derivatives in the treatment of malaria in China.Trans. R. Soc. Trop. Med. Hyg. 1994; 88: S5-S6Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 6.Teuscher F. et al.Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure.J. Infect. Dis. 2010; 202: 1362-1368Crossref PubMed Scopus (149) Google Scholar, 7.Witkowski B. et al.Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism.Antimicrob. Agents Chemother. 2010; 54: 1872-1877Crossref PubMed Scopus (196) Google Scholar]. Early in its development, Chinese investigators already suggested that artemisinin should be used as combination therapy with one or more partner drugs [4.Li G.Q. et al.Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria.Lancet. 1984; 2: 1360-1361Abstract PubMed Scopus (94) Google Scholar]. Artesunate combined with mefloquine was one of the first artemisinin-based combination therapies (ACTs) evaluated, showing that a 3-day regimen was safe, well tolerated, and highly effective in treating uncomplicated multidrug-resistant P. falciparum malaria in Western Thailand [8.Nosten F. et al.Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination.J. Infect. Dis. 1994; 170: 971-977Crossref PubMed Scopus (225) Google Scholar]. Combining two existing drugs led to high efficacy rates despite the drugs not being fully effective on their own because of their pharmacokinetic properties (artemisinins) or parasite resistance (mefloquine). In the first 3 days of treatment the total parasite load is rapidly reduced by the highly potent yet quickly eliminated artemisinin component, and the remaining parasites are subsequently killed by the less potent yet long-lasting partner drug [9.White N.J. Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization.Antimicrob. Agents Chemother. 2013; 57: 5792-5807Crossref PubMed Scopus (63) Google Scholar,10.White N.J. The parasite clearance curve.Malar. J. 2011; 10: 278Crossref PubMed Scopus (133) Google Scholar]. In 2006 the World Health Organization (WHO) recommended ACTs as global first-line treatments for P. falciparum malaria Health Organization for the of Scholar]. ACTs are recommended by the and Health Organization for the of Scholar]. Health Organization on Artemisinin and Scholar]. with of and in and the of ACTs in the of malaria and the in which the of the global malaria burden et combinations for treatment of Full Text Full Text PDF PubMed Scopus Google Scholar, et of malaria on Plasmodium falciparum in and PubMed Scopus Google Scholar, Health Organization World Scholar]. clearance of parasites artemisinins from Artemisinin resistance in P. falciparum is by parasite clearance treatment with an et the of parasite clearance in falciparum the parasite clearance J. 2011; 10: PubMed Scopus Google and was first in in [1.Dondorp A.M. et al.Artemisinin resistance in Plasmodium falciparum malaria.N. Engl. J. Med. 2009; 361: 455-467Crossref PubMed Scopus (2339) Google Scholar]. artemisinin in the GMS as a parasite clearance half-life of h, spread the GMS and is in of infections in and et of treatment failure in Plasmodium falciparum malaria in and a and Infect. Dis. Full Text Full Text PDF PubMed Scopus Google Scholar]. The in with in in a also a with in the of the P. falciparum F. et of Plasmodium falciparum Scopus Google Scholar, B. et for the of Plasmodium falciparum malaria in and Infect. Dis. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, J. et artemisinin resistance in Plasmodium falciparum PubMed Scopus Google which the of artemisinin resistance at a in et of in Plasmodium falciparum in J. PubMed Scopus Google Scholar]. to artemisinin to a of parasites the 3 days of treatment, which in an in parasite from to parasites to the partner drug A.M. et to and multidrug-resistant falciparum Full Text Full Text PDF PubMed Scopus Google Scholar]. The partner drug will parasites but selection of Artemisinin resistance by selection for partner drug resistance for mefloquine and for and and also and resulted in high failure rates of ACTs et of treatment failure in Plasmodium falciparum malaria in and a and Infect. Dis. Full Text Full Text PDF PubMed Scopus Google et efficacy of artemisinin combination therapy against P. falciparum malaria on the the of parasite Infect. Dis. PubMed Scopus Google Scholar, et resistance in Plasmodium falciparum malaria in a Infect. Dis. Full Text Full Text PDF PubMed Scopus Google Scholar, et al.Treatment failure of for Plasmodium falciparum Infect. Dis. PubMed Scopus Google Scholar, et al.Clinical and in resistance of Plasmodium falciparum to in Infect. Dis. PubMed Scopus Google Scholar]. efficacy the that and are currently in Health Organization on Artemisinin and all of have shown efficacy in et of for the treatment of uncomplicated falciparum malaria in Med. PubMed Scopus Google Scholar, et of the efficacy of and mefloquine combination for the treatment of uncomplicated falciparum malaria in Med. PubMed Scopus Google Scholar, R. et and of for treatment of uncomplicated Plasmodium falciparum malaria in Western Agents Chemother. 60: PubMed Scopus Google Scholar]. The three ACTs in that treatment the for efficacy for a first-line antimalarial drug, are and Health Organization on Artemisinin and Scholar]. is the for artemisinin and partner drug resistance to spread to and to the spread of resistance to and that to of in et spread of PubMed Scopus Google Scholar, The impact of resistance in J. Trop. Med. Hyg. PubMed Scopus Google Scholar, et and in Plasmodium PubMed Scopus Google Recent from of in and in of P. falciparum to in a or will have to be et with artemisinin resistance in Infect. Dis. PubMed Scopus Google et of Plasmodium falciparum malaria in Engl. J. Med. PubMed Scopus Google Scholar]. in the have from but in with rates or in that are not with artemisinin as the Health Organization World et of with artemisinin resistance at and a near complete of falciparum malaria in of 10: PubMed Scopus Google Scholar, et of Plasmodium falciparum Engl. J. Med. PubMed Scopus Google Scholar, et Plasmodium falciparum with high rates, Infect. Dis. PubMed Scopus Google Scholar]. from and of to be emergence of parasites with are a for a of and showing an in have from patients in L.C. et emergence in of Plasmodium falciparum with in artemisinin PubMed Scopus Google Scholar]. at three in a of parasites with a single a with parasites with parasite clearance and first of emergence and spread of artemisinin resistance in et and of in Plasmodium falciparum parasites in Med. PubMed Scopus Google and P. falciparum parasites to have in the and on at but the from in and by the parasites spread the et and in Plasmodium PubMed Scopus Google with a and to in was in countries and the with to a in in some The impact of resistance in J. Trop. Med. Hyg. PubMed Scopus Google Scholar]. and parasites and spread from to the combination was to safe, and available drugs for the treatment of P. falciparum malaria The of drug-resistant R. Soc. Trop. Med. Hyg. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. P. falciparum in Western probably already in the early even artemisinin-based combination therapies (ACTs) recommended by the World Health Organization as first-line is likely to have resulted from their as at in with parasite by drugs A.M. et al.Artemisinin and for Rev. 2010; PubMed Scopus Google the of P. falciparum et and of multidrug-resistant malaria in a Infect. Dis. Full Text Full Text PDF PubMed Scopus (105) Google et of resistance to antimalarial drugs in the Greater Mekong an Infect. Dis. Full Text Full Text PDF PubMed Scopus Google Scholar]. spread the GMS an to malaria from the to prevent spread to and to have of P. falciparum in and more emergence of artemisinin resistance in et with artemisinin resistance in Infect. Dis. PubMed Scopus Google et of Plasmodium falciparum malaria in Engl. J. Med. PubMed Scopus Google et and of in Plasmodium falciparum parasites in Med. PubMed Scopus Google Scholar]. provide a for the emergence of artemisinin In was until the first-line in the of an for the emergence and spread of artemisinin In to high which to an reduction in P. falciparum an drug on the remaining parasites, a with a of P. falciparum with its emergence in the and of the for treatments for multidrug-resistant P. P. falciparum parasites to have in the and on at but the from in and by the parasites spread the et and in Plasmodium PubMed Scopus Google with a and to in was in countries and the with to a in in some The impact of resistance in J. Trop. Med. Hyg. PubMed Scopus Google Scholar]. and parasites and spread from to the combination was to safe, and available drugs for the treatment of P. falciparum malaria The of drug-resistant R. Soc. Trop. Med. Hyg. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. P. falciparum in Western probably already in the early even artemisinin-based combination therapies (ACTs) recommended by the World Health Organization as first-line is likely to have resulted from their as at in with parasite by drugs A.M. et al.Artemisinin and for Rev. 2010; PubMed Scopus Google Scholar]. the of P. falciparum et and of multidrug-resistant malaria in a Infect. Dis. Full Text Full Text PDF PubMed Scopus (105) Google et of resistance to antimalarial drugs in the Greater Mekong an Infect. Dis. Full Text Full Text PDF PubMed Scopus Google Scholar]. spread the GMS an to malaria from the to prevent spread to and to have of P. falciparum in and more emergence of artemisinin resistance in et with artemisinin resistance in Infect. Dis. PubMed Scopus Google et of Plasmodium falciparum malaria in Engl. J. Med. PubMed Scopus Google et and of in Plasmodium falciparum parasites in Med. PubMed Scopus Google Scholar]. provide a for the emergence of artemisinin In was until the first-line in the of an for the emergence and spread of artemisinin In to high which to an reduction in P. falciparum an drug on the remaining parasites, a with a of P. falciparum with its emergence in the and of the for treatments for multidrug-resistant P. treatments are in artemisinin and partner drug resistance are must be effective, well tolerated, safe, and less likely to to antimalarial drugs in the development is to and will the are that new compounds will not be available for deployment the in development for PubMed Scopus Google Scholar, et and of J. PubMed Scopus Google Scholar, N.J. new treatment resistance in PubMed Scopus Google Scholar]. the window of to prevent of multidrug-resistant malaria by a likely of multidrug-resistant falciparum malaria infections is of patients with falciparum malaria not to therapy is et to treatment in two patients with malaria on the J. PubMed Scopus Google Scholar]. In the high treatment failure with the then first-line antimalarial in and was with an in falciparum malaria existing antimalarials in could their efficacy A.M. et to and multidrug-resistant falciparum Full Text Full Text PDF PubMed Scopus Google et al.Artemisinin and resistance in Plasmodium Full Text Full Text PDF PubMed Scopus Google Scholar]. is to prolong the of 3-day of by a 3-day of ACTs was fully effective, even in with artemisinin resistance et of artemisinin resistance in Plasmodium falciparum malaria.N. Engl. J. Med. PubMed Scopus Google Scholar]. could likely in adherence to the therapy patients which less likely to complete a treatment ACTs could be used as first-line treatment, or at the same et as the in drug resistance with first-line Med. PubMed Scopus Google Scholar]. deployed the first-line treatment be at or resistance to one of the partner drugs a In ACTs at the same could be the as the on partner drugs the for a parasite to resistance to the partner drugs in the of the of resistance to partner drug, is the drugs in F. N.J. combination treatment of falciparum J. Trop. Med. Hyg. PubMed Scopus Google N.J. antimalarial drug resistance with combination Google Scholar]. and of is and in In the GMS, to a new to be in two could not be multidrug-resistant parasites already spread et of treatment failure in Plasmodium falciparum malaria in and a and Infect. Dis. Full Text Full Text PDF PubMed Scopus Google Scholar]. to prolong the of existing antimalarials is to two partner drugs with artemisinins in artemisinin-based combination therapies triple-drug combinations are for treatment of and infections Health Organization on the of for and Health Organization on Scholar]. to could efficacy of the drugs longer even in the of artemisinin partner drugs are to a parasite are and are more to the development of drugs for TACTs to be to provide elimination or more the of the must be to in parasites to a single drug the of resistance to drug must at be not As with first-line the of resistance to of the partner drugs highly effective treatment to the The to Artemisinin the and efficacy of two TACTs et artemisinin-based combination therapies artemisinin-based combination therapies for uncomplicated Plasmodium falciparum a Full Text Full Text PDF PubMed Scopus Google Scholar]. on their pharmacokinetic mefloquine was to the and was to to the TACTs. combinations also of resistance in and mefloquine and et resistance in Plasmodium falciparum malaria in a Infect. Dis. Full Text Full Text PDF PubMed Scopus Google P. et that Plasmodium falciparum in Western is in to Agents Chemother. PubMed Scopus Google Scholar, et Plasmodium falciparum to artemisinin-based combination PubMed Scopus Google Scholar, et in Plasmodium falciparum resistance and resistance parasite that treatment for P. falciparum malaria and J. Trop. Med. Hyg. PubMed Scopus Google Scholar, et resistance and its with in and of Plasmodium falciparum from Trop. 2011; PubMed Scopus Google Scholar, et resistance in Plasmodium falciparum and Full Text Full Text PDF PubMed Scopus Google Scholar, et selection of Plasmodium falciparum by Infect. Dis. PubMed Scopus Google Scholar]. TACTs highly In and in of was effective, whereas efficacy of in the same will be TACTs safe and well tolerated, of and with that TACTs could an effective to drug-resistant malaria and could be available and have of which also a combination et of properties and J. PubMed Scopus Google et and of Chemother. 2013; PubMed Scopus Google Scholar]. the with and the with the is currently in of ACTs the and in and of and from and and will likely with the of TACTs. the of TACTs and to pharmacokinetic drug and and J. et of and in in Agents Chemother. 2010; 54: PubMed Scopus Google Scholar, J. et and of in with uncomplicated falciparum PubMed Scopus Google Scholar, The of on the antimalarial efficacy of a of Med. 2013; 10 (discussion PubMed Scopus Google Scholar]. of any of the of the TACTs parasite clearance and and selection of drug-resistant parasites The of on the antimalarial efficacy of a of Med. 2013; 10 (discussion PubMed Scopus Google Scholar, et and drug 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, N.J. et and are an of drug J. 2009; PubMed Scopus Google Scholar, et in PubMed Scopus Google Scholar]. but drug in the drugs in the combination to be B. et study of the and pharmacokinetic and mefloquine in Agents Chemother. PubMed Scopus Google Scholar]. of will the with the development of the TACTs. most antimalarials currently in are the of drugs. of TACTs be of an and a partner drug should be as a more rapidly available in TACTs are in the The and of all currently available ACTs and antimalarial are well of antimalarial drugs are and of are also in malaria infections and in an of the of Combining an with drug will likely in or the of to the antimalarial is to of and to are or mefloquine, and have as of and but all well used in Health Organization The of et of the and antimalarial a Med. PubMed Scopus Google Scholar]. The is used as a for the of The patients to and that the of mefloquine to not the of the that is of et artemisinin-based combination therapies artemisinin-based combination therapies for uncomplicated Plasmodium falciparum a Full Text Full Text PDF PubMed Scopus Google Scholar]. of to the of the to of and not on the and efficacy of in in from will available in the near and trials on TACTs will not be to the of the deployment of TACTs to prevent or delay the development of antimalarial drug and could provide In the identified the of pharmacokinetic and pharmacodynamic in the of drug-resistant malaria et of drug-resistant the of drug elimination R. Soc. PubMed Scopus Google Scholar]. In a in the development and of to antimalarial drug development, to for development, of drug resistance and the spread of and transmission to drug deployment and et the impact of artemisinin and partner drug resistance in J. PubMed Scopus Google et to drug development for malaria Full Text Full Text PDF PubMed Scopus Google Scholar]. used to that for malaria treatment be and the of ACTs be et al.Artemisinin the and J. PubMed Scopus Google Scholar]. of be in the impact of antimalarial therapies, are and to could the likely impact of TACTs as first-line antimalarial treatments in will the of TACTs to delay the emergence and spread of and falciparum malaria in the of transmission and of drug Pharmacokinetic for partner drugs could the dose of the partner drugs at which is drug are high to parasites that not eliminated in the first 3 days of treatment, the window of as the that parasites are to drug et the efficacy of artemisinin-based combination therapies for treating Plasmodium falciparum malaria patients Agents Chemother. PubMed Scopus Google Scholar]. In could the of TACTs in the of TACTs ACTs the and malaria and from antimalarial drug of malaria and elimination have but to be addressed to to the of an et of malaria and J. PubMed Scopus Google Scholar]. TACTs as first-line treatment in in the of failure an should a in a three drugs for malaria of two two drugs and the of a drug in some with the considerations of antimalarial drug the for the will have to be on and be N.J. drug PubMed Scopus Google Scholar]. and the of ACTs antimalarials in et to the effective treatment and of malaria in of Health 2009; PubMed Scopus Google Scholar]. that TACTs not be and with to of and adherence. of the of from patients and to and malaria will to to deployment of TACTs in of TACTs is likely to be in the impact of TACTs to prevent or delay The emergence of artemisinin resistance in the and on the deployment of TACTs in TACTs more The to ACTs for the treatment of malaria as one of the by malaria in the in malaria the and deployment of artemisinin-based combination J. Trop. Med. Hyg. PubMed Scopus Google Scholar]. as the that from to ACTs the effective of antimalarial of in an of Scholar]. In to the and a in and deployment of and not to and et of malaria treatment from PubMed Scopus Google et in a development a malaria treatment PubMed Scopus Google Scholar]. of in and of have also are in the to new antimalarials and their and to be at an early in to for of TACTs. will have to be that in and TACTs are is a the period treatment of ACTs for the treatment of Health Organization World Scholar]. malaria is a of and and antimalarial drug to be for the and and for as and and will be to in The for TACTs is drugs with resistance are the that resistance will to any of its will be antimalarials are the of and or delay of antimalarial resistance is for the of malaria In with high failure rates, as effective treatment with TACTs will which is by the of recrudescent infections that more infections and are more in uncomplicated Plasmodium falciparum malaria treatment with artemisinin combination a and of Med. PubMed Scopus Google N.J. and antimalarial The transmission of antimalarial drug resistance in Plasmodium Trop. PubMed Scopus Google Scholar]. should be addressed to the development, and of TACTs (see the combinations of drugs and the dose of is drugs in combinations requires by Early of a for on the of which for malaria drugs, as the will likely the of the development will be to have in the for of TACTs or the of TACTs in treatment will be that study and are and and early of and the is on the and of TACTs is in in the of treatments with TACTs should be to their deployment in In the GMS, artemisinin and partner drug resistance TACTs the efficacy of ACTs will be a for their not yet by resistance a will be on the and of as a new to the of with drug resistance that the of antimalarial drugs Triple combination treatments should be to delay the emergence of the J. PubMed Scopus Google N.J. Triple combination treatments should be to delay the emergence of J. PubMed Scopus Google Scholar]. reduced P. falciparum transmission in of and the of artemisinin and partner drug emergence and spread for a of which treatment will which will the of patients treatment, and will antimalarial drug on the parasite drug the for antimalarial drug resistance to and reduced the of of reduced will be infections with the of the parasite in the the that When transmission will also to partner and The and the reduction in P. falciparum malaria have for the emergence and spread of artemisinin resistance in et and of in Plasmodium falciparum parasites in Med. PubMed Scopus Google Scholar]. prevent the spread or emergence of multidrug-resistant falciparum malaria the deployment of As deployment of TACTs to be will a to and and provide of the of TACTs in to and by is being addressed by the of Triple which a by with in and to and in the of and the of a of malaria a Health Organization for et on malaria Full Text Full Text PDF PubMed Scopus Google antimalarial drugs should and should not be combined in artemisinin-based combination therapies (TACTs), pharmacokinetic drug resistance and is the dose of drugs in of drugs and can be can be for to will be the for TACTs with to drug and are the and efficacy of TACTs as mefloquine, and in in be safe for which is for of high malaria ACTs could have an efficacy in the of artemisinin In are TACTs more TACTs in with existing resistance the selection of multidrug-resistant is the of TACTs in emergence or of antimalarial resistance in antimalarial resistance is not established, and will on and transmission is the of the of an development and of the the in the of the TACTs be in ACTs are to patients to TACTs that have more ACTs to prevent emergence of resistance in the can deployment of TACTs be addressed at an early antimalarial drugs should and should not be combined in artemisinin-based combination therapies (TACTs), pharmacokinetic drug resistance and is the dose of drugs in of drugs and can be can be for to will be the for TACTs with to drug and are the and efficacy of TACTs as mefloquine, and in in be safe for which is for of high malaria ACTs could have an efficacy in the of artemisinin In are TACTs more TACTs in with existing resistance the selection of multidrug-resistant is the of TACTs in emergence or of antimalarial resistance in antimalarial resistance is not established, and will on and transmission is the of the of an development and of the the in the of the TACTs be in ACTs are to patients to TACTs that have more ACTs to prevent emergence of resistance in the can deployment of TACTs be addressed at an early are to and the for are to J. for the of a in which the of P. falciparum parasites, their life is or as a of parasites which from by an of the for the in of a drug to be reduced by from its The of antimalarial drugs is from (artemisinins) to for is for parasites to resistance to drugs with a longer at in the parasite life a of the at which parasites are from the treatment with an antimalarial is as the of the parasite against in is the in which an can be in of h is to be of artemisinin resistance in a of the in In an is as the from the of the to the of the of is to be an of of drugs. as and rates and are used in of antimalarial drugs. of with of parasites from the are from which a new must be by that the of parasites from the and infections are the an in drug used to artemisinin resistance in P. is from drug in that parasites are and to artemisinins a of their life cycle in to in trials per a to the efficacy of antimalarial drugs. are in countries to the efficacy of drugs being used as first-line treatments or their in of patients in a a of resistance and should a in the first-line treatment

Topics & Concepts