The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network

WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia, International Centre for Diarrheal Diseases and Research, Bangladesh (icddr,b), Dhaka, Bangladesh.
WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia, Internal Medical Services, Ballarat Health Services, Ballarat, Victoria, Australia.
Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia.
ICAP at Mailman School of Public Health, Columbia University, New York, New York, USA.
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
National Institute of Malaria Research, Dwarka, New Delhi, India.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR.
Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Department of Bacterial and Parasitic Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand, Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia.
Medical Research Council Unit The Gambia at LSTMH, Fajara, The Gambia.
Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Australia.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Australian Defence Force Malaria and Infectious Disease Institute, Enoggera, Brisbane, Australia.
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
Universidade de São Paulo. Insituto de Ciências Biomédicas. Departametno de Parasitologia. São Paulo, SP, Brasil.
US President's Malaria Initiative, Malaria Branch, US Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America, Global Health Group, University of California San Francisco, San Francisco, California, USA.
Médecins Sans Frontieres, Brussels, Belgium.
Melbourne Medical School–Western Health, The University of Melbourne, Melbourne, Australia, Western Health Chronic Disease Alliance, Sunshine Hospital, St Albans, Melbourne, Australia.
Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Doenças Parasitárias. Rio de Janeiro, RJ, Brasil / Ministério da Saúde. Rede Amazônica para a Vigilância da Resistência antimalária de drogas. Iniciativa Malária Amazônica. Cruzeiro do Sul, AC, Brasil.
Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Australia, Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR, Institute of Research and Education Development (IRED), University of Health Sciences, Ministry of Health, Vientiane, Lao PDR.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Australia, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia.
Division of Population Health and Immunity, The Walter & Eliza Hall Institute of Medical Research, Melbourne, Australia, Department of Medical Biology, University of Melbourne, Melbourne, Australia, Parasites and Insect Vectors Department, Institut Pasteur, Paris, France.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam.
MARIB - Malaria Research Initiative Bandarban, Vienna, Austria.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
Mimika District Hospital, Timika, Indonesia, Timika Malaria Research Programme, Papuan Health and Community Development Foundation, Timika, Indonesia, Paediatric Research Office, Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia.
Division of Medicine, United States Army Research Institute of Infectious Diseases, Ft. Detrick, Maryland, USA.
Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Myanmar Oxford Clinical Research Unit, Yangon, Myanmar, Medical Action Myanmar, Yangon, Myanmar
Department of Bacterial and Parasitic Diseases, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom, Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia.
WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom, Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia, Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Abstract

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.

Keywords in Portuguese

Plasmodium Vivax parasitaemia
P. falciparum malaria
Meta-análise
Pacientes
Rede mundial de resistência antimalária
Dados individuais
Risco

Keywords

Plasmodium Vivax parasitaemia
P. falciparum malária
Individual patient data
Meta analysis
Risk
wWorldwide antimalarial resistance network

Publisher

Public Library of Science

Citation

HOSSAIN, Mohammad S. et al. The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network. Plos Medicine, v. 17, n. 11, p. 1-26, Nov. 2020.

DOI

10.1371/journal.pmed.1003393

ISSN

1549-1277

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/44858

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Open access

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