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

Autoři: Robert J. Commons aff001;  Julie A. Simpson aff003;  Kamala Thriemer aff001;  Tesfay Abreha aff004;  Ishag Adam aff005;  Nicholas M. Anstey aff001;  Ashenafi Assefa aff006;  Ghulam R. Awab aff007;  J. Kevin Baird aff009;  Bridget E. Barber aff001;  Cindy S. Chu aff010;  Prabin Dahal aff010;  André Daher aff014;  Timothy M. E. Davis aff017;  Arjen M. Dondorp aff007;  Matthew J. Grigg aff001;  Georgina S. Humphreys aff013;  Jimee Hwang aff018;  Harin Karunajeewa aff020;  Moses Laman aff017;  Kartini Lidia aff023;  Brioni R. Moore aff017;  Ivo Mueller aff020;  Francois Nosten aff010;  Ayodhia P. Pasaribu aff007;  Dhelio B. Pereira aff028;  Aung P. Phyo aff012;  Jeanne R. Poespoprodjo aff030;  Carol H. Sibley aff013;  Kasia Stepniewska aff010;  Inge Sutanto aff034;  Guy Thwaites aff010;  Tran T. Hien aff010;  Nicholas J. White aff007;  Timothy William aff011;  Charles J. Woodrow aff007;  Philippe J. Guerin aff010;  Ric N. Price aff001
Působiště autorů: Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia aff001;  WorldWide Antimalarial Resistance Network (WWARN), Clinical module, Darwin, Northern Territory, Australia aff002;  Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia aff003;  ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia aff004;  Faculty of Medicine, University of Khartoum, Khartoum, Sudan aff005;  Malaria and Neglected Tropical Diseases Research Team, Bacterial, Parasitic, Zoonotic Diseases Research Directorate, Ethiopian Public Health Institute, Addis Ababa, Ethiopia aff006;  Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand aff007;  Nangarhar Medical Faculty, Nangarhar University, Jalalabad, Afghanistan aff008;  Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia aff009;  Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom aff010;  Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia aff011;  Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand aff012;  WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom aff013;  Institute of Drug Technology (Farmanguinhos), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil aff014;  Vice‑presidency of Research and Reference Laboratories, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil aff015;  Liverpool School of Tropical Medicine, Liverpool, United Kingdom aff016;  Medical School, The University of Western Australia, Fremantle Hospital Unit, Fremantle, Western Australia, Australia aff017;  U.S. President's Malaria Initiative, Malaria Branch, U.S. Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America aff018;  Global Health Group, University of California San Francisco, San Francisco, California, United States of America aff019;  Division of Population Health and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia aff020;  Western Centre for Health Research and Education, Western Health, Melbourne, Victoria, Australia aff021;  Papua New Guinea Institute of Medical Research, Madang, Madang Province, Papua New Guinea aff022;  The Department of Pharmacology and Therapy, Faculty of Medicine, Nusa Cendana University, Kupang, Indonesia aff023;  School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia aff024;  Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia aff025;  Parasites and Insect Vectors Department, Institut Pasteur, Paris, France aff026;  Medical Faculty, Universitas Sumatera Utara, Medan, North Sumatera, Indonesia aff027;  Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM), Porto Velho, Rondônia, Brazil aff028;  Universidade Federal de Rondônia (UNIR), Porto Velho, Rondônia, Brazil aff029;  Mimika District Hospital, Timika, Indonesia aff030;  Timika Malaria Research Programme, Papuan Health and Community Development Foundation, Timika, Indonesia aff031;  Paediatric Research Office, Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia aff032;  Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America aff033;  Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia aff034;  Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam aff035;  Gleneagles Hospital, Kota Kinabalu, Sabah, Malaysia aff036
Vyšlo v časopise: 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. PLoS Med 16(10): e32767. doi:10.1371/journal.pmed.1002928
Kategorie: Research Article



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.


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.

Klíčová slova:

Antimalarials – Dose prediction methods – Malaria – Plasmodium – Primaquine – Systematic reviews – Chloroquine


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