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Antimicrobial Agents and Chemotherapy, November 2007, p. 4090-4097, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00486-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Clinical and Pharmacological Determinants of the Therapeutic Response to Dihydroartemisinin-Piperaquine for Drug-Resistant Malaria{triangledown}

R. N. Price,1,2* A. R. Hasugian,3 A. Ratcliff,1 H. Siswantoro,3 H. L. E. Purba,3 E. Kenangalem,4,5 N. Lindegardh,2,6 P. Penttinen,7,8 F. Laihad,9 E. P. Ebsworth,7,8 N. M. Anstey,1 and E. Tjitra3

International Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia,1 Centre for Vaccinology & Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, Oxford, United Kingdom,2 National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia,3 Menzies School of Health Research-National Institute of Health Research and Development Malaria Research Program, Timika, Indonesia,4 District Health Office, Timika, Papua, Indonesia,5 Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand,6 Public Health and Malaria Control Department, PT Freeport Indonesia, Tembagapura, Papua, Indonesia,7 International SOS, Tembagapura, Papua, Indonesia,8 Directorate General of Disease Control and Environmental Health, Ministry of Health, Jakarta, Indonesia9

Received 10 April 2007/ Returned for modification 8 July 2007/ Accepted 2 September 2007

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 concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum, 83 with Plasmodium vivax, and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [CI]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivax. After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 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 old and 22% (31/140) of adults (P = 0.04), even though the overall dose (mg per kg of body weight) 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 (hazard ratio [HR] = 6.6 [95% CI: 1.9 to 23]; P = 0.003) or P. vivax (HR = 9.0 [95% CI: 2.3 to 35]; 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 dose revision may be warranted in this age group.

* Corresponding author. Mailing address: Menzies School of Health Research, PO Box 41096, Casuarina, Darwin, NT 0811, Australia. Phone: (61) 8 8922 8197. Fax: (61) 8 8922 8429. E-mail: ricprice{at}doctors.org.uk

{triangledown} Published ahead of print on 10 September 2007.

Antimicrobial Agents and Chemotherapy, November 2007, p. 4090-4097, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00486-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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