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Safety and Efficacy of Dihydroartemisinin-Piperaquine in Falciparum Malaria: A Prospective Multi-Centre Individual Patient Data Analysis

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  • Julien Zwang
  • Elizabeth A Ashley
  • Corine Karema
  • Umberto D'Alessandro
  • Frank Smithuis
  • Grant Dorsey
  • Bart Janssens
  • Mayfong Mayxay
  • Paul Newton
  • Pratap Singhasivanon
  • Kasia Stepniewska
  • Nicholas J White
  • François Nosten

Abstract

Background: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda. Methods and Findings: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28–63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6–99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site). Conclusions: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3.

Suggested Citation

  • Julien Zwang & Elizabeth A Ashley & Corine Karema & Umberto D'Alessandro & Frank Smithuis & Grant Dorsey & Bart Janssens & Mayfong Mayxay & Paul Newton & Pratap Singhasivanon & Kasia Stepniewska & Nic, 2009. "Safety and Efficacy of Dihydroartemisinin-Piperaquine in Falciparum Malaria: A Prospective Multi-Centre Individual Patient Data Analysis," PLOS ONE, Public Library of Science, vol. 4(7), pages 1-13, July.
    • Handle: RePEc:plo:pone00:0006358
    DOI: 10.1371/journal.pone.0006358
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    References listed on IDEAS

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    1. Tanilu Grande & Andrea Bernasconi & Annette Erhart & Dioni Gamboa & Martin Casapia & Christopher Delgado & Kathy Torres & Caterina Fanello & Alejandro Llanos-Cuentas & Umberto D'Alessandro, 2007. "A Randomised Controlled Trial to Assess the Efficacy of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Falciparum Malaria in Peru," PLOS ONE, Public Library of Science, vol. 2(10), pages 1-7, October.
    2. Moses R Kamya & Adoke Yeka & Hasifa Bukirwa & Myers Lugemwa & John B Rwakimari & Sarah G Staedke & Ambrose O Talisuna & Bryan Greenhouse & François Nosten & Philip J Rosenthal & Fred Wabwire-Mangen & , 2007. "Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial," PLOS Clinical Trials, Public Library of Science, vol. 2(5), pages 1-9, May.
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