Efficacy and safety of dihydroartemisinin-piperaquine in Indonesian children infected with uncomplicated Plasmodium falciparum and Plasmodium vivax
Abstract
Background Dihydroartemisinin-piperaquine (DPQ) has been used since 2006 in Papua, Indonesia and is planned as an alternative artemisinin-based combination therapy for wider use in Indonesia. Confirmation of the drug’s efficacy and safety in children outside Papua is needed.
Objective To measure the day-42 clinical and parasitological efficacy of DPQ in children with uncomplicated falciparum and vivax malaria.
Methods This cross-sectional and observational study was held in Kalimantan and Sulawesi in 2010. Seventy and sixty children under 15 years of age with uncomplicated falciparum and vivax malaria were selected according to the 2003 WHO protocol for monitoring therapeutic efficacy of antimalarial treatments and was confirmed by microscopy and PCR. All subjects were treated with DPQ based on a dosage regimen of dihydroartemisinin 2-4 mg/kg BW/dose and piperaquine 16-32 mg/kg BW/dose, in single daily doses for 3 days and closely observed for 42 days. Data was analyzed using intention-to-treat (ITT) and per protocol (PP) populations.
Results The mean fever and asexual parasite clearance times were 1.0 day and 1.6 days, respectively, in children with uncomplicated falciparum malaria, and 1.1 days and 1.2 days, respectively, in children with uncomplicatedvivax malaria. Clinical symptoms reduced over 50% by day 7. Hemoglobin recoveries showed improvement on days 14, 28 and 42, at 70.6%, 83.8%and 89.1%, respectively, in the falciparum malaria group, and 60.3%, 65,5% and 83.6%, respectively, in thevivax malaria group. Adequate clinical and parasitological response to DPQ on day 42 in the ITT and PP populations were reported as 98.6% (95% CI 92.3 to 99.7%) and 100% (95% CI 94.7 to 100%), respectively, in the falciparum group, and 91.7% (95% CI 81.9 to 96.4%) and 96.5% (95% CI 88.1 to 99.0%), respectively, the vivax group. Mild adverse events commonly noted were cough, abdominal pain, diarrhea, anorexia, and vomiting.
Conclusion DPQ was effective against falciparum and vivax malaria with adequate clinical and parasitological response of ≥ 95%, rapid fever and asexual parasite clearance, good hematological recovery and mild adverse events.
References
2. Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, Cisse Met, et al. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial. Lancet. 2002;359:1365-72.
3. Tjitra E and Maladi. Artesunate plus amodiaquine vs artemisinin plus piperaquine for treatment falciparum and vivax malaria: preliminary findings. Artemisinin compounds clinical trial information exchange workshop; 2005 July 8, Bangkok, Thailand.
4. Setyaningrum E, Sutanto I, Fauzia M, Subandryo HD, Santoso B, Rosidi, et al. Efficacy of artesunate-amodiaquine in uncomplicated falciparum malaria cases, Lampung Province, Sumatra, Indonesia. In: Improving insight of antimicrobials and anti-parasitics towards better management of infectious diseases. Proceedings from the 6th Jakarta Antimicrobial Update 2005 in conjunction with the 1st International Parasitic Disease Update; 2005 April 16-17; Jakarta, Indonesia. Division of Tropical and Infectious Diseases, Department of Medicine, Faculty of Medicine University of Indonesia, Cipto Mangunkusumo Hospital 2005, Jakarta.
5. Hasugian AR, Purba HLE, Kenangalem E, Wuwung RM, Ebsworth EP, Maristela R, et al. Dihydroartemisinin-piperaquine versus artesunate-amodiaquine: superior efficacy and post-treatment prophylaxis against multidrug-resistant Plasmodium falciparum and Plasmodium vivax malaria. Clin Infect Dis. 2007;44:1067-74.
6. R Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung RM, Laihad F, et al. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet. 2007;369:757-65.
7. World Health Organization. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. In: WHO/HTM/RBM/ 2003.50. Geneva: WHO; 2003.p.9-36
8. Ministry of Health. Malaria case management guideline. Directorate General of Disease Control and Environmental Health. Jakarta, 2009.p.12-20
9. World Health Organization. Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite populations; Informal consultation organized by the Medicines for Malaria Venture and cosponsored by the World Health Organization, 2007 May 29–31; Amsterdam, Netherlands. Geneva: World Health Organization.p.13-41
10. Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, 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;41:425-32.
11. Karema C, Fanello CI, van Overmeir C, van Geertruyden JP, van Doren W, Ngamije D, et al. Safety and efficacy of dihydroartemisinin/piperaquine (artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg. 2006;100:1105–11.
12. Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial. PLoS Clin Trials. 2007;2:20.
13. Myint HY, Ashley EA, Day NP, Nosten F, White NJ. Efficacy and safety of dihydroartemisinin-piperaquine. Trans R Soc Trop Med Hyg. 2007;101:858–66.
14. Zongo I, Dorsey G, Rouamba N, Dokomajilar C, Sere Y, Rosenthal J, et al. Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Clin Infect Dis. 2007;45:1453–61.
15. Yeka A, Dorsey G, Kamya MRMR, Talisuna A, Lugemwa M, Rwakimari JB, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda. PLoS ONE. 2008;3:2390.
16. Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo APP, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010;10:673–81.
17. M Mayxay M, Keomany S, Khanthavong M, Souvannasing P, Stepniewska K, Khomthilath T, et al. A phase III, non-inferiority trial to assess the efficacy and safety of dihydroartemisinin-piperaquine in comparison with artesunate-mefloquine in patients with uncomplicated Plasmodium falciparum malaria in Southern Laos. Am J Trop Med Hyg. 2010;83:1221-9.
18. Awab GR, Pukrittayakamee S, Imwong M, Dondorp AM, Woodrow CJ, Lee SJ, et al.RDihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial. Malar J. 2010;9:105.
19. Valecha N, Phyo AP, Mayxay M, Newton PN, Krudsood S, Keomany S, et al. An open-label, randomised study of dihydroartemisinin-piperaquine versus artesunate-mefloquine for falciparum malaria in Asia. PLoS ONE. 2010;5:e11880.
20. World Health Organization. Guidelines for the treatment of malaria. 2nd ed. Geneva: World Health Organization; 2010. p. 14-22
21. Arinaitwe E, Sandison TG, Wanzira H, Kakuru A, Homsy J, Kalamya J, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. Clin Infect Dis. 2009;49:1629–37.
22. Nambozi M, Geertruyden JPV, Hachizovu S, Chaponda M, Mukwamataba D, Mulenga M, et al. Safety and efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Zambian children. Malar J. 2011;10:50.
23. Denis MB, Davis TME, Hewitt S, Incardona S, Nimol K, Fandeur T, et al. Efficacy and safety of dihydroartemisinin-piperaquine (artekin) in Cambodian children and adults with uncomplicated falciparum malaria. Clin Infect Dis. 2002;35:1469–76.
24. Ratcliff A, Siswantoro H, Kenangalem E, Wuwung RMRM, Brockman A, Edstein MD, et al. Therapeutic response of multidrug-resistant Plasmodium falciparum and P.vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia. Trans R Soc Trop Med Hyg. 2007;101:351-9.
25. Hung TY, Davis TM, Ilett KF, Karunajeewa H, Hewitt S, Denis MB, et al. Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol. 2004;57:253–62.
26. World Health Organization. Global plan for artemisinin resistance containment (GPARC). Geneva: World Health Organization; 2011. p. 16
27. Kumar N. and Zheng H. Stage-specific gametocytocidal effect in vitro of the antimalaria drug qinghaosu on Plasmodium falciparum. Parasitol Res. 1990;76:214-8.
28 Targett G, Drakeley C, Jawara M, von Seidlein L, Coleman R, Deen J, et al. Artesunate reduces but does not prevent post-treatment transmission of Plasmodium falciparum to Anopheles gambiae. J Infect Dis. 2001;183:1254-9.
29. Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, Chongsuphajaisiddhi T, et al. Effects of artemisinin derivatives on malaria transmissibility. Lancet. 1996;347:1654-8.
30. Watkins WM, Mosobo M. Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life. Trans R Soc Trop Med Hyg. 1993;87:75–8.
31. White NJ. How antimalarial drug resistance affects post-treatment prophylaxis. Malar J. 2008;7:9.
32. Stepniewska K, White NJ. Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrob Agents Chemother. 2008;52:1589–96.
Authors who publish with this journal agree to the following terms:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
Accepted 2016-10-11
Published 2011-12-31
