AAC Accepts, published online ahead of print on 10 September 2007

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00486-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin–piperaquine for drug resistant malaria

R N Price^*, A R Hasugian, A Ratcliff, H Siswantoro, H LE Purba, E Kenangalem, N Lindegardh, P Penttinen, F Laihad, E P Ebsworth, N M Anstey, and E Tjitra

International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia, Centre for Vaccinology & Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, UK, National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia, Menzies School of Health Research-National Institute of Health Research and Development Malaria Research Program, Timika, Indonesia, District Health Office, Timika, Papua, Indonesia, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand, Public Health and Malaria Control Department, PT Freeport, Indonesia, Tembagapura, Papua, Indonesia, International SOS, Tembagapura, Papua, Indonesia, Directorate General of Disease Control and Environmental Health, Ministry of Health, Jakarta, Indonesia

^* To whom correspondence should be addressed. Email: ricprice{at}doctors.org.uk.

Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine levels were assessed on day 7 and day 28 and the cumulative risk of parasitological failure calculated at day 42 using survival analysis. Of the 598 patients in the evaluable population 342 had infections with P. falciparum, 83 with P. vivax and 173 with a mixture of both species. The unadjusted cumulative risk of recurrence was 7.0% [95%CI: 4.6-9.4%] for P. falciparum and 8.9% [95%CI: 6.0-12] for P. vivax. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% [95%CI: 0.1-2.1]. The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years and 22% (31/140) of adults (p=0.04), even though the overall mg per kg dose in children was 9% higher than that in adults (p<0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (Adjusted Hazard Ratio= 6.6 [95%CI: 1.9-23]; p=0.003) or P. vivax (AHR=9.0 [95%CI: 2.3-35] for P. vivax; p=0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that an increase in the dose maybe warranted in this age group.

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