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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

Commons RJ 1 , Simpson JA 2 , Thriemer K 1 , Abreha T 3 , Adam I 4 , Anstey NM 1 Show all authors , Assefa A 5 , Awab GR 6 , Baird JK 7 , Barber BE 1 , Chu CS 8 , Dahal P 8 , Daher A 9 , Davis TME 10 , Dondorp AM 6 , Grigg MJ 1 , Humphreys GS 11 , Hwang J 12 , Karunajeewa H 13 , Laman M 10 , Lidia K 14 , Moore BR 10 , Mueller I 13 , Nosten F 8 , Pasaribu AP 6 , Pereira DB 15 , Phyo AP 16 , Poespoprodjo JR 17 , Sibley CH 11 , Stepniewska K 8 , Sutanto I 18 , Thwaites G 8 , Hien TT 8 , White NJ 6 , William T 19 , Woodrow CJ 6 , Guerin PJ 8 , Price RN 1

Affiliations 

  • 1 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
  • 2 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  • 3 ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia
  • 4 Faculty of Medicine, University of Khartoum, Khartoum, Sudan
  • 5 Malaria and Neglected Tropical Diseases Research Team, Bacterial, Parasitic, Zoonotic Diseases Research Directorate, Ethiopian Public Health Institute, Addis Ababa, Ethiopia
  • 6 Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  • 7 Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia
  • 8 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
  • 9 Institute of Drug Technology (Farmanguinhos), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
  • 10 Medical School, The University of Western Australia, Fremantle Hospital Unit, Fremantle, Western Australia, Australia
  • 11 WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom
  • 12 U.S. President's Malaria Initiative, Malaria Branch, U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
  • 13 Division of Population Health and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia
  • 14 The Department of Pharmacology and Therapy, Faculty of Medicine, Nusa Cendana University, Kupang, Indonesia
  • 15 Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM), Porto Velho, Rondônia, Brazil
  • 16 Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
  • 17 Mimika District Hospital, Timika, Indonesia
  • 18 Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
  • 19 Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia
PLoS Med, 2019 Oct;16(10):e1002928.
PMID: 31584960 DOI: 10.1371/journal.pmed.1002928

Abstract

BACKGROUND: Artemisinin-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 FINDINGS: Clinical 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 < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.

CONCLUSIONS: In 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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