REVIEWS Artemisinin resistance: current status and scenarios for containment Arjen M. Dondorp*‡, Shunmay Yeung*§, Lisa White*‡, Chea Nguon§, Nicholas P.J. Day*‡, Duong Socheat§|| and Lorenz von Seidlein*¶ Abstract | Artemisinin combination therapies are the first-line treatments for uncomplicated Plasmodium falciparum malaria in most malaria-endemic countries. Recently, partial artemisinin-resistant P. falciparum malaria has emerged on the Cambodia–Thailand border. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years, and the availability of substandard artemisinins, have probably been the main driving force in the selection of the resistant phenotype in the region. A multifaceted containment programme has recently been launched, including early diagnosis and appropriate treatment, decreasing drug pressure, optimising vector control, targeting the mobile population, strengthening management and surveillance systems, and operational research. Mathematical modelling can be a useful tool to evaluate possible strategies for containment. Parenteral In nearly all countries in which malaria is endemic, antimalarial properties (artemisinin) was identified, and Administered by injection. artemisinin combination therapies (ACT) are now the several more potent derivatives were synthesized, includ- recommended first-line therapy for uncomplicated ing artesunate, artemether and dihydroartemisinin11 Plasmodium falciparum malaria, a policy endorsed by (FIG. 1). Artemisinin derivatives have an excellent safety the WHO1. This change in policy followed a period profile in the treatment of malaria, a rapid onset of action of increasing failure rates with chloroquine and later and are active against the broadest range of stages in the sulphadoxine–pyrimethamine treatment, which arose life cycle of Plasmodium spp. compared with other anti- from the development of resistant P. falciparum strains. malarials11,12 (FIG. 2). Artemisinins also kill immature and The spread and increased levels of resistance to the developing gametocytes, the sexual stages that are essen- generally available and affordable drugs resulted in an tial for transmission13,14, thereby reducing gametocyte increase in the number of deaths caused by malaria in carriage and infectivity. *Mahidol Oxford Research Unit, Faculty of Tropical children under 5 years of age in sub-Saharan Africa In the blood, the dihydroartemisinin derivatives Medicine, Mahidol University, during a period when overall childhood mortality was artesunate, artemether and artemotil are quickly and Bangkok 10400, Thailand. decreasing2–4. This trend has now been reversed with completely hydrolysed back to dihydroartemisinin, ‡Centre for Tropical Medicine, the introduction of ACTs and other control measures, which has a short plasma half-life of ~ 1 hour10. A once Churchill Hospital, University of specifically the widespread use of insecticide-treated or twice a day dosing regimen with artemisinin deriva- Oxford, Oxford OX3 7LJ, UK. §London School of Hygiene bed nets. A marked decrease in malaria burden has been tives results in a reduction of four orders of magnitude and Tropical Medicine, observed in several Asian and African regions, where of the asexual parasite biomass per 48-hour treatment London, WC1E 7HT, UK. these effective control measures have been deployed cycle (FIG. 2). Despite this remarkable antimalarial activ- ||The National Center for actively5–8. In addition, parenteral artesunate, an artemi- ity, artemisin derivative monotherapy for 7 days covering Parasitology Entomology and Malaria Control, Phnom Penh, sin derivative, became the treatment of choice for severe 3 cycles of the asexual life cycle of the parasite is needed 12 Cambodia. malaria in adults after it was shown to reduce mortality to completely eliminate a biomass of 10 parasites, ¶Joint Malaria Project, Tanga, by 35% compared with quinine9. which corresponds to a parasitaemia of ~2% in an Tanzania. Artemisinins extracted from the ubiquitous annual adult11. The short half-life of artemisinin derivatives Correspondence to A.M.D. wormwood Artemisia annua have been used in tradi- minimizes the period available for the selection of resist- e-mail: [email protected] 15 doi:10.1038/nrmicro2331 tional Chinese medicine for more than 2,000 years for ant strains (known as the selective window) . However, 10 Published online the treatment of febrile illnesses . In the 1970s the chem- there is still the potential for the emergence of resist- 8 March 2010 ical structure of a sesquiterpene peroxide with powerful ant strains when artemisinin derivatives are deployed 272 | APRIL 2010 | VOLUME 8 www.nature.com/reviews/micro © 2010 Macmillan Publishers Limited. All rights reserved FOCUS ON ANTIMICROBIAL RESISREVIEWSTANCE Emergence of resistant P. falciparum strains O O The first reports of higher recrudescence rates of P. fal - O O ciparum malaria after treatment with ACTs emerged O O from observational data collected in Cambodia since O O 2004 (REFS 21,22 ). It was not clear initially whether these O O high failure rates resulted from resistance to artemisi- CH3 nins, their partner drugs or unusual host or pharmacoki- Artemisinin Artemether netic factors23,24. A study carried out in 2006 and 2007 in Battambang province, Cambodia, showed that a minor- ity of patients with uncomplicated P. falciparum malaria O O harboured parasites with decreased in vitro sensitivity to O O O O artesunate and showed delayed parasite clearance times O O in the presence of apparently adequate plasma drug con- centrations after treatment with artesunate in a dose of O O 25 O COO– 4 mg per kg per day for 7 days . Conclusive evidence came from a recent study com- Artesunate Artemotil paring the therapeutic responses to artesunate in patients Figure 1 | Chemical structure of artemisinins. Artemisinin with uncomplicated P. falciparum malaria in Pailin, is the compound that is produced by the plant Artemisia western Cambodia, and Wang Pha, western Thailand, annua. The derivatives arthemether and artesunate have where artemisinin derivatives remain effective26 (FIG. 3). better bioavailability than artemisininNatur eand Re viearews used | Micr obiology Clearance rates were much slower in western Cambodia clinically in artemisinin combination therapy. Artemotil and showed little heterogeneity (FIG. 4). Specifically, after (also known as arteether) is infrequently used. artesunate monotherapy in a dose of 2 mg per kg per day for 7 days or artenusate in a dose of 4 mg per kg as monotherapies in areas of increasing drug pressure, per day for 3 days followed by mefloquine in a dose of so researchers suggested more than a decade ago that 25 mg per kg per day, the median parasite clearance artemisinin derivatives should be used only in combi- time was 84 hours (interquartile range (IQR) = 60 to nation with partner drugs in ACTs16. The artemisinin 96) in Pailin compared with 48 hours (IQR = 36 to 66) component of ACTs rapidly kills the bulk of the organ- in Wang Pha (p=0.001), with similar drug concentra- isms and a partner drug with a longer plasma half-life tion profiles in both sites. The difference in clearance eliminates the remaining parasites. This not only opti- rates was not explained by genetic polymorphisms in mizes the therapeutic benefit, but also mutually protects the P. falciparum genes pfcrt (chloroquine resistance both components of the ACT and minimizes the risk transporter gene), pfmdr1 (multidrug resistance gene 1) of resistant parasites emerging and spreading17. In the or pfserca (a sacroplasmic reticulum Ca2+ ATPase) — absence of an efficient partner drug, repeated exposure which had been suggested previously as the targets of to artemisinin monotherapies at subtherapeutic doses, artemisinins — or amplification in pfmdr1. Heritability especially in hyperparasitaemic patients and over studies suggest that the observed artemisinin resist- prolonged periods of time, will provide a risk for the ance phenotype of the parasites has a genetic basis and emergence of resistance18. thus is expected to spread within parasite populations After a lengthy delay before general acceptance, that live where artemisinins are deployed unless asso- ACTs have now been implemented as first-line treat- ciated fitness costs of the putative resistance mutation ment in the national malaria control programmes of or mutations outweigh selective benefits27. The study most malaria-endemic countries19. Deployment in the shows that in patients treated with artesunate, geneti- private sector, however, lags far behind. To ensure the cally identical parasite strains (defined by microsatellite use of the combination, rather than the individual com- typing) strongly cluster in patients with slow versus fast ponents, fixed-dose ACTs have been developed, includ- parasite clearance rates. To date, the molecular basis for ing artemether–lumefantrine, artesunate–mefloquine the resistance mechanism remains unknown, although and artesunater–amodiaquine. Dihydroartemisinin– intensive molecular and phenotypical characterization piperaquine and artesunate–pyronaridine are in is under way. advanced stages of clinical testing and drug registration. The short and mid-term pipeline for antimalarial drug Development of resistance development depends on artemisinin derivatives20; los- Several factors may have contributed to the emer- ing the artemisinin derivatives because of P. falciparum gence of reduced artemisinin sensitivity in Cambodia. drug resistance