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See Online for appendix

For the online parasite clearance estimator see http:// www.wwarn.org/toolkit/datamanagement/parasiteclearance-estimator

the National Institute for Allergy and Infectious Diseases Institutional Review Board. Adults or parents of child participants gave written informed consent. The appendix shows patient characteristics. 87% (26/30) of patients were men and the median age was 25 years (inter-quartile range 2032 years). 70% (21/30) of patients had at least one erythrocyte polymorphism. 33% (10/30) of patients had P falciparum gametocytaemia and 10% (3/10) had Plasmodium vivax parasitaemia. Most patients had prostration, repetitive vomiting, or cessation of eating and drinking, or a combination of these manifestations. Two patients had severe anaemia or renal insuciency; none had cerebral malaria or died. The median haemoglobin concentration was 140 g/L (interquartile range 120150 g/L). The initial parasite density (median 141 744 parasites per L, interquartile range 88 873264 631 parasites per L) was higher than it was in our recent study of patients with uncomplicated malaria (n=168, 50 498 parasites per L, interquartile range 27 940123 276 parasites per L, p<00001).1 After initial parasite density was counted, patients received intramuscular artemether (32 mg/kg on day 0, then 16 mg/kg on days 14) and orally administered meoquine (25 mg/kg over days 5 and 6). Parasite densities were counted from thick blood lms every 6 h until parasites were undetectable1 and the data were used to create parasite clearance curves.4 The parasite clearance halflife was calculated with use of the Worldwide Antimalarial Resistance Network online parasite clearance estimator.5 The parasite clearance time (median 96 h, interquartile range 66116 h) was longer than that in our recent study of patients with uncomplicated malaria (n=167, 78 h, interquartile range 6090 h, p=0007)1 and ranged from 48 h to 150 h. One patient

with an initial parasite density of 528 000 parasites per L received artemisininpiperaquine (Artequick, Artepharm Co, Guangzhou, China) at 168 h and cleared her parasitaemia at 204 h. As was expected, the parasite clearance time correlated with the initial parasite density (Spearmans rank r=0501, p=0005). The parasite clearance half-life (geometric mean 590 h, 95% CI 502693) was similar to that in patients with uncomplicated malaria in our recent study (n=168, 585 h, 95% CI 554 618, p=0781)1 and did not correlate with age, haemoglobin type, haemoglobin concentration, or initial parasite density. In this letter, we report baseline parasite clearance rates in patients with severe malaria in western Cambodia. Similar half-life values in patients with severe or uncomplicated malaria suggest that artemether treatment for severe malaria does not accelerate parasite clearance rates compared with artesunate treatment for uncomplicated malaria. Future eorts should monitor parasite clearance and recrudescence rates in patients with severe malaria harbouring large parasite biomasses, which may be more likely to yield artemisinin-resistant parasites.
This work was funded by the Intramural Research Program of the National Institute for Allergy and Infectious Diseases, National Institutes of Health.

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Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 71725. White N. The parasite clearance curve. Malar J 2011; 10: 278. Flegg JA, Guerin PJ, White NJ, Stepniewska K. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J 2011; 10: 339.

Artemisinin resistance or artemisinin-based combination therapy resistance?

In his recent Comment in The Lancet Infectious Diseases, Joel Breman discussed parasite resistance to artemisinin-based combination therapy (ACT) and the heritability of this resistance.1,2 The dierences between artemisinin resistance and resistance to ACT (also termed ACT resistance) merit further clarication. Researchers have used many methods to try to prove the existence of artemisinin resistance. Lengthening of the parasite clearance time suggests artemisinin resistance. Amaratunga and colleagues2 delayed meoquine administration to exclude the contribution of meoquine in parasite clearance during the rst 72 hthe period most relevant to artemisinin action. This approach deviates from the standard treatment schedule for the purpose of their studyie, to investigate the genetic basis of artemisinin resistance. This study design does not have a primary aim to show ACT resistance, which leads to ACT failures. The term ACT resistance is used loosely and often interchangeably with artemisinin resistance, although it should not be. Artemisinin resistance could contribute to ACT failure, but the combination of artemisinin with an ecacious partner drug can improve cure rates to an adequate level.3 Evidence of artemisinin resistance has been scarce so far, and only a working
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Chanaki Amaratunga, Sivanna Mao, Sokunthea Sreng, Seila Suon, *Rick M Fairhurst
rfairhurst@niaid.nih.gov
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (CA, RMF); Sampov Meas Referral Hospital, Pursat, Cambodia (SM); National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia (SSr, SSu) 1 Amaratunga C, Sreng S, Suon S, et al. Artemisinin-resistant Plasmodium falciparum malaria in Pursat, western Cambodia: a parasite clearance rate study. Lancet Infect Dis 2012; 12: 85158. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 2000; 94 (suppl 1): S190.

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denition of such resistance exists. The longer parasite clearance times reported in the Mekong subregion could be due to a non-progressive weakening of artemisinin activity. ACTs are still highly ecacious in most of this subregion, especially in Laos, Burma, and Vietnam.4 One exception is the decreasing ecacy of artesunatemeoquine at the CambodianThai border. Two locations in western Cambodia are good examples of ACT resistance, where, despite the policy switch from failing artesunatemeoquine to dihydroartemisininpiperaquine treatment, the 42 day treatment ecacies are only 7389%, and more than 40% of patients have positive parasitaemia on day 3.3 Existing meoquine resistance and the unregulated availability of dihydroartemisininpiperaquine in the private sector for the past 10 years could explain its failure.

Scientists are trying to elucidate the basis of artemisinin resistance, whereas malaria control programmes focus on ACT resistance, especially the morbidity and mortality associated with inecacy of the combined drugs. WHO, senior health authorities, and donor agencies have correctly emphasised artemisinin resistance as a public health warning, support for which is essential for maintenance of parasite susceptibility to artemisinins at the highest possible level or for elimination of those parasites. In view of the scarce choices of appropriate partner drugs, if artemisinin resistance becomes established, it will negatively aect global achievements in malaria control. I agree with Bremans concern about Africa, where great care should be taken in deployment of ACTs.5 The availability of ACTs in Africa from drug vendors without parasitological diagnosis is a dangerous problem.

I declare that I have no conicts of interest.

Chansuda Wongsrichanalai
dr.chansuda@gmail.com
2121 Sul Ross Street, San Angelo, TX 76904, USA 1 Breman JG. Resistance to artemisinin-based combination therapy. Lancet Infect Dis 2012; 12: 82022. Amaratunga C, Sreng S, Suon S, et al. Artemisinin-resistant Plasmodium falciparum malaria in Pursat province, western Cambodia: a parasite-clearance-rate study. Lancet Infect Dis 2012; 12: 85158. World Health Organization Global Malaria Programme. Update on artemisinin resistanceApril 2012. http://www.who.int/ malaria/publications/atoz/arupdate042012. pdf (accessed Oct 15, 2012). World Health Organization Global Malaria Programme. The status of drug-resistant malaria along the ThailandMyanmar border. Revised 9 May 2012. http://www.who.int/ malaria/publications/atoz/drug_resistance_ myanmar_thailand_border_may_2012.pdf (accessed Oct 15, 2012). Wongsrichanalai C, Thimasarn K, Sirichaisinthop J. Antimalarial drug combination policy: a caveat. Lancet 2000; 355: 224547.

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