PLoS Medicine (Oct 2019)

The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis.

  • Robert J Commons,
  • Julie A Simpson,
  • Kamala Thriemer,
  • Tesfay Abreha,
  • Ishag Adam,
  • Nicholas M Anstey,
  • Ashenafi Assefa,
  • Ghulam R Awab,
  • J Kevin Baird,
  • Bridget E Barber,
  • Cindy S Chu,
  • Prabin Dahal,
  • André Daher,
  • Timothy M E Davis,
  • Arjen M Dondorp,
  • Matthew J Grigg,
  • Georgina S Humphreys,
  • Jimee Hwang,
  • Harin Karunajeewa,
  • Moses Laman,
  • Kartini Lidia,
  • Brioni R Moore,
  • Ivo Mueller,
  • Francois Nosten,
  • Ayodhia P Pasaribu,
  • Dhelio B Pereira,
  • Aung P Phyo,
  • Jeanne R Poespoprodjo,
  • Carol H Sibley,
  • Kasia Stepniewska,
  • Inge Sutanto,
  • Guy Thwaites,
  • Tran T Hien,
  • Nicholas J White,
  • Timothy William,
  • Charles J Woodrow,
  • Philippe J Guerin,
  • Ric N Price

DOI
https://doi.org/10.1371/journal.pmed.1002928
Journal volume & issue
Vol. 16, no. 10
p. e1002928

Abstract

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BackgroundArtemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and findingsClinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p ConclusionsIn this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.