Correspondence

Antimalarial Therapies in Children from Papua New Guinea

N Engl J Med 2009; 360:1254-1255March 19, 2009

Article

To the Editor:

In their article on antimalarial combination therapies, Karunajeewa et al. (Dec. 11 issue)1 conclude that artemether–lumefantrine has more favorable efficacy than dihydroartemisinin–piperaquine, even though fat was given with the treatment only in the artemether–lumefantrine group and there was no significant difference in the primary end point. Their per-protocol analysis with a high dropout rate from a small sample results in overestimation of the risk of treatment failure and wide 95% confidence intervals (6.4% to 20.0%). We reanalyzed data from 981 children younger than 5 years of age who were treated with dihydroartemisinin–piperaquine in seven clinical trials in Indonesia, Thailand, Uganda, and Burkina Faso. Dihydroartemisinin–piperaquine was administered with milk or a biscuit. Overall, the recrudescence rate at day 42 was 3.1% (95% confidence interval, 1.9 to 4.3), ranging from 0 to 7.1%. The risk of recurrent malaria was significantly reduced after treatment with dihydroartemisinin–piperaquine as compared with artemether–lumefantrine (odds ratio, 0.51; P<0.001).

Dihydroartemisinin–piperaquine is a highly effective treatment for multidrug-resistant falciparum malaria in young children and provides clinically significant post-treatment prophylaxis.2-4 We recommend that both dihydroartemisinin–piperaquine and 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@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 Medicine for Malaria Venture (MMV). No other potential conflict of interest relevant to this letter was reported.

5 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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

3. 3

   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 | Web of Science | Medline

4. 4

   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

5. 5

   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
   CrossRef | Web of Science | Medline

Author/Editor Response

Enhanced piperaquine bioavailability with fat coadministration1 was reported after our trial had started. There were no food-specific dosing recommendations for dihydroartemisinin–piperaquine then or subsequently.2 Other studies have shown excellent efficacy when fat coadministration was not required, and no pharmacokinetic factors, including baseline parasitemia, were independent determinants of the efficacy of dihydroartemisinin–piperaquine in our trial. Nevertheless, because low plasma piperaquine concentrations at day 7 predict recrudescence3 and relevant bioavailability data are from healthy adults,1 pharmacokinetic studies (including tolerability and safety) determining optimal fat intake in children with falciparum malaria would be valuable. We provided the justification for our sample size, analyzed and interpreted efficacy using current World Health Organization (WHO) guidelines,4 and presented best-case and worst-case scenarios for the effect of attrition on treatment outcome (see the Supplementary Appendix, available with the full text of the article at NEJM.org). The lower 95% confidence limit for treatment failure with dihydroartemisinin–piperaquine at day 42 in per-protocol analyses (6.4%) was above the limit (<5%) recommended by the WHO for adoption of new therapy.4 The discordance between this finding and low failure rates in other countries is likely to reflect the epidemiologic complexity of malaria and underscores the need for valid local efficacy trials before new treatments are deployed.

Timothy M.E. Davis, D.Phil., M.B., B.S.
University of Western Australia, Crawley, WA 6009, Australia
tdavis@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

4 References

1. 1

   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
   CrossRef | Web of Science | Medline

2. 2

   Duo-Cotecxin antimalarial. Beijing: Beijing Holley-Cotec Pharmaceuticals Co. Ltd. (Accessed February 18, 2009, at http://www.cotecxin.com/en/products/antimalarial/Combination/2008-09-24/Combination35i74i271.html.)
   

3. 3

   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
   CrossRef | Web of Science | Medline

4. 4

   Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: World Health Organization, 2003. (WHO/HTM/RBM/2003.50.)
   

Citing Articles (3)

Citing Articles

1. 1

   Nicola Gargano, Fabio Cenci, Quique Bassat. (2011) Antimalarial efficacy of piperaquine-based antimalarial combination therapies: facts and uncertainties. Tropical Medicine & International Health 16:12, 1466-1473
   CrossRef

2. 2

   I. Adam, M. T. Salah, H. G. Eltahir, A. H. Elhassan, K. A. Elmardi, E. M. Malik. (2010) Dihydroartemisinin–piperaquine <I>versus</I> artemether–lumefantrine, in the treatment of uncomplicated <I>Plasmodium</I> <I>falciparum</I> malaria in central Sudan. Annals of Tropical Medicine and Parasitology 104:4, 319-326
   CrossRef

3. 3

   Umberto DʼAlessandro. (2009) Progress in the development of piperaquine combinations for the treatment of malaria. Current Opinion in Infectious Diseases 22:6, 588-592
   CrossRef