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LETTERSSevere Malaria NotResponsive to ArtemisininDerivatives in Man Returningfrom Angola to VietnamPascal Ringwald, Arjen M. DondorpAuthor affiliations: World Health Organization, GenevaSwitzerland (P. Ringwald); Faculty of Tropical Medicine,Mahidol University, Bangkok, Thailand (A.M. Dondorp)DOI: http://dx.doi.org/10.3201/eid2107.141448To the Editor: Partial artemisinin-resistant Plasmodiumfalciparum malaria, characterized by delayed parasite clearanceafter treatment with artesunate or artemisinin-basedcombination therapy, was first detected in western Cambodiaand has now spread to or emerged de novo in 5 countries ofthe Greater Mekong Subregion (GMS) (1). However, mostreported cases of malaria have been in Africa, and detectingartemisinin and multidrug resistance in Africa will have consequencesfor policy and containment plans (2).Thus, vigilant monitoring is pivotal, and it is thereforewith great interest that we read the case report on a patientin Vietnam with severe P. falciparum malaria, acquired inAngola in 2013, that was not responsive to artesunate orseveral other antimalarial combinations (3). We believethat there are several issues that challenge the conclusionthat artemisinin resistance has reached Angola: 1) the phenotypicand genotypic characteristics of the infecting strainin this patient were very different from artemisinin-resistantstrains in the GMS; 2) pharmacokinetic issues cannotbe ruled out; and 3) perhaps of most relevance, the studydocuments severely delayed clearance of multiple strains inthis polyclonal P. falciparum infection, suggesting splenichypofunction as an important contributor.The parasite clearance half-life calculated with theWorld Health Organization (WHO) online slope analyzerfrom the log linear segment of the clearance curve afterstart of artesunate therapy was 102.5 hours, which is ≈10times longer than observed in the most artemisinin-resistantparasites in Cambodia. Postpublication genotyping of theinfecting strain provided by the authors to WHO showed awild-type Kelch (K13) gene, which is a recently discoveredmolecular marker for artemisinin resistance strongly correlatedto the resistant phenotype in the GMS (1).No pharmacokinetic assessment was made, and subtherapeuticartesunate and dihydroartemisinin (as well asclindamycin, piperaquine, quinine, and doxycycline) bloodconcentrations cannot be excluded. The intravenous artesunateregimen used differed from the WHO guideline of2.4 mg/kg on admission, after 12 h, then daily. Pharmacokineticmodeling of the split doses used in the describedcase indicate that this dosing schedule results in 2 clones of parasites persisting >1 week aftertreatment with multiple antimalarial drugs. It seems veryunlikely that this patient harbored multiple highly artemisinin-resistantparasite strains. Dead circulating intraerythrocyticparasites in patients who have hyposplenia can berecognized morphologically, but the article does not providedetails on this.Circulation of multidrug resistant malarial strains insub-Saharan Africa can have disastrous consequences, andit is critical to detect its arrival at an early stage. The casereport by Van Hong et al. implies the unlikely event of independentemergence of multidrug resistant strains in atraveler from Vietnam in Angola, without evidence of localdeclining artemisinin-based combination therapy efficacy.WHO and partners are investigating the phenotype andgenotype of parasite strains from the same geographic areain Angola to address the concerns raised above. We believethat this single case report is insufficient to raise the alarm.References1. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P,Suon S, et al.; Tracking Resistance to Artemisinin Collaboration(TRAC). Spread of artemisinin resistance in Plasmodiumfalciparum malaria. N Engl J Med. 2014;371:411–23.http://dx.doi.org/10.1056/NEJMoa13149812. Dondorp AM, Fairhurst RM, Slutsker L, MacArthur JR,Breman JG, Guerin PJ, et al. The threat of artemisinin-resistantmalaria. N Eng J Med. 2011;365;12:1073–75. http://dx.doi.org/10.1056/NEJMp11083221264 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015