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Title: The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network
Authors: Mohammad S. Hossain
Robert J. Commons
Nicholas M. Douglas
Kamala Thriemer
Bereket H. Alemayehu
Chanaki Amaratunga
Anupkumar R. Anvikar
Elizabeth A. Ashley
Puji B.S. Asih
Verena I. Carrara
Chanthap Lon
Umberto D’Alessandro
Timothy M.E. Davis
Arjen M. Dondorp
Michael D. Edstein
Rick M. Fairhurst
Marcelo U. Ferreira
Jimee Hwang
Bart Janssens
Harin Karunajeewa
Jean R. Kiechel
Simone Ladeia-Andrade
Moses Laman
Mayfong Mayxay
Rose McGready
Brioni R. Moore
Ivo Mueller
Paul N. Newton
Nguyen T. Thuy-Nhien
Harald Noedl
Francois Nosten
Aung P. Phyo
Jeanne R. Poespoprodjo
David L. Saunders
Frank Smithuis
Michele D. Spring
Kasia Stepniewska
Seila Suon
Yupin Suputtamongkol
Din Syafruddin
Hien T. Tran
Neena Valecha
Michel van Herp
Michele van Vugt
Nicholas J. White
Philippe J. Guerin
Julie A. Simpson
Ric N. Price
Oxford University Clinical Research Unit
Melbourne Medical School
Melbourne School of Population and Global Health
Medecins Sans Frontieres, Brussels
Papua New Guinea Institute of Medical Research
Eijkman Institute for Molecular Biology
Hasanuddin University
Universitas Gadjah Mada
Shoklo Malaria Research Unit
The University of Western Australia
Curtin University
Sunshine Hospital
Columbia University Irving Medical Center
Walter and Eliza Hall Institute of Medical Research
University of Melbourne
Fundacao Oswaldo Cruz
Menzies School of Health Research
National Institute of Malaria Research India
University of California, San Francisco
Centers for Disease Control and Prevention
National Institute of Allergy and Infectious Diseases (NIAID)
Armed Forces Research Institute of Medical Sciences, Thailand
Mahosot Hospital, Lao
Mahidol University
Ballarat Health Services
Faculty of Medicine, Siriraj Hospital, Mahidol University
International Centre for Diarrhoeal Disease Research Bangladesh
Slotervaart Hospital
Nuffield Department of Medicine
United States Army
Universidade de Sao Paulo - USP
Institut Pasteur, Paris
Drugs for Neglected Diseases initiative (DNDi)
Myanmar Oxford Clinical Research Unit
University of Health Sciences
Australian Defence Force Malaria and Infectious Disease Institute
Mimika District Hospital
Ministry of Health of Brazil
Medical Action Myanmar
Armed Forces Research Institute of Medical Sciences
Papuan Health and Community Development Foundation
WorldWide Antimalarial Resistance Network (WWARN)
National Center for Parasitology, Entomology and Malaria Control
Keywords: Medicine
Issue Date: 19-Nov-2020
Citation: PLoS Medicine. Vol.17, No.11 (2020)
Abstract: © 2020 Public Library of Science. All rights reserved. Background There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. Methods and findings A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years; range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. Conclusions In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.
ISSN: 15491676
Appears in Collections:Scopus 2020

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