To the Editor: In their article on antimalarial combinationtherapies, Karunajeewa et al. (Dec. 11 issue)1 conclude thatartemether–lumefantrine has more favorable efficacy thandihydroartemisinin–piperaquine, even though fat was givenwith the treatment only in the artemether–lumefantrinegroup and there was no significant difference in the primaryend point. Their per-protocol analysis with a high dropout ratefrom a small sample results in overestimation of the risk oftreatment failure and wide 95% confidence intervals (6.4% to20.0%). We reanalyzed data from 981 children younger than 5years of age who were treated with dihydroartemisinin–piperaquinein seven clinical trials in Indonesia, Thailand, Uganda, andBurkina Faso. Dihydroartemisinin–piperaquine was administeredwith milk or a biscuit. Overall, the recrudescence rate at day42 was 3.1% (95% confidence interval, 1.9 to 4.3), ranging from0 to 7.1%. The risk of recurrent malaria was significantly reducedafter treatment with dihydroartemisinin–piperaquine ascompared with artemether–lumefantrine (odds ratio, 0.51;P<0.001).
Dihydroartemisinin–piperaquine is a highly effective treatmentfor multidrug-resistant falciparum malaria in young childrenand provides clinically significant post-treatment prophylaxis.2,3,4We recommend that both dihydroartemisinin–piperaquineand artemether–lumefantrine be given with fat (milk, biscuit,or other food) to increase bioavailability.5
Ric N. Price, M.D. Menzies School of Health Research Darwin, NT 0811, Australia rnp{at}menzies.edu.au
Grant Dorsey, M.D., Ph.D. University of California San Francisco, CA 94110
Francois Nosten, M.D., Ph.D. Shoklo Malaria Research Unit Mae Sod 63110, Thailand
Drs. Price and Nosten report serving as consultants to Medicinefor Malaria Venture (MMV). No other potential conflict of interestrelevant to this letter was reported.
References
Karunajeewa HA, Mueller I, Senn M, et al. A trial of combination antimalarial therapies in children from Papua New Guinea. N Engl J Med 2008;359:2545-2557. [Free Full Text]
Ratcliff A, Siswantoro H, Kenangalem E, et al. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet 2007;369:757-765. [CrossRef][Web of Science][Medline]
Yeka A, Dorsey G, Kamya MR, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda. PLoS ONE 2008;3:e2390-e2390. [CrossRef][Medline]
Ashley EA, McGready R, Hutagalung R, et al. A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis 2005;41:425-432. [CrossRef][Web of Science][Medline]
Sim IK, Davis TM, Ilett KF. Effects of a high-fat meal on the relative oral bioavailability of piperaquine. Antimicrob Agents Chemother 2005;49:2407-2411. [Free Full Text]
The authors reply: Enhanced piperaquine bioavailability withfat coadministration1 was reported after our trial had started.There were no food-specific dosing recommendations for dihydroartemisinin–piperaquinethen or subsequently.2 Other studies have shown excellent efficacywhen fat coadministration was not required, and no pharmacokineticfactors, including baseline parasitemia, were independent determinantsof the efficacy of dihydroartemisinin–piperaquine in ourtrial. Nevertheless, because low plasma piperaquine concentrationsat day 7 predict recrudescence3 and relevant bioavailabilitydata are from healthy adults,1 pharmacokinetic studies (includingtolerability and safety) determining optimal fat intake in childrenwith falciparum malaria would be valuable. We provided the justificationfor our sample size, analyzed and interpreted efficacy usingcurrent World Health Organization (WHO) guidelines,4 and presentedbest-case and worst-case scenarios for the effect of attritionon treatment outcome (see the Supplementary Appendix, availablewith the full text of the article at NEJM.org). The lower 95%confidence limit for treatment failure with dihydroartemisinin–piperaquineat day 42 in per-protocol analyses (6.4%) was above the limit(<5%) recommended by the WHO for adoption of new therapy.4The discordance between this finding and low failure rates inother countries is likely to reflect the epidemiologic complexityof malaria and underscores the need for valid local efficacytrials before new treatments are deployed.
Timothy M.E. Davis, D.Phil., M.B., B.S. University of Western Australia Crawley, WA 6009, Australia tdavis{at}cyllene.uwa.edu.au
Harin A. Karunajeewa, M.B., B.S. Western Hospital Footscray, VIC 3011, Australia
Ivo Mueller, Ph.D. Papua New Guinea Institute of Medical Research Madang 511, Papua New Guinea
References
Sim IK, Davis TM, Ilett KF. Effects of a high-fat meal on the relative oral bioavailability of piperaquine. Antimicrob Agents Chemother 2005;49:2407-2411. [Free Full Text]
Price RN, Hasugian AR, Ratcliff A, et al. Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria. Antimicrob Agents Chemother 2007;51:4090-4097. [Free Full Text]
Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: World Health Organization, 2003. (WHO/HTM/RBM/2003.50.)
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