Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis

Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. The funders of the study had no role in study design, data collection, data analysis, data inter...

Descripción completa

Detalles Bibliográficos
Autores: Mehdipour, Parinaz, Rajasekhar, Megha, Dini, Saber, Zaloumis, Sophie, Abreha, Tesfay, Adam, Ishag, Awab, Ghulam Rahim, Baird, J. Kevin, Brasil, Larissa Wanderley, Chu, Cindy S., Cui, Liwang, Daher, André Bastos, Gomes, Margarete do Socorro Mendonça, Gonzalez Ceron, Lilia, Hwang, Jimee, Karunajeewa, Harin, Lacerda, Marcus Vinícius Guimarães de, Andrade, Simone Ladeia, Leslie, Toby, Ley, Benedikt, Lidia, Kartini, Llanos Cuentas, Alejandro, Longley, Rhea J., Monteiro, Wuelton Marcelo, Pereira, Dhelio Batista, Rijal, Komal Raj, Saravu, Kavitha, Sutanto, Inge, Taylor, Walter R. J., Thanh, Pham Vinh, Thriemer, Kamala, Vieira, José Luiz Fernandes, White, Nicholas J., Zuluaga Idarraga, Lina M., Guerin, Philippe J., Price, Ric N., Simpson, Julie A., Commons, Robert J.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:Brasil
Institución:Fundação Oswaldo Cruz (FIOCRUZ)
Repositorio:Repositório Institucional da FIOCRUZ (ARCA)
Idioma:inglés
OAI Identifier:oai:arca.fiocruz.br:icict/63076
Acceso en línea:https://arca.fiocruz.br/handle/icict/63076
Access Level:acceso abierto
Palabra clave:Malaria
Plasmodium vivax
Adherence
Primaquine
Rate of recurrence
Supervision
id BR_e4d5a0bbcb4aa39cf50a4241069e3642
oai_identifier_str oai:arca.fiocruz.br:icict/63076
network_acronym_str BR
network_name_str Brasil
repository_id_str
dc.title.none.fl_str_mv Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
title Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
spellingShingle Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
Mehdipour, Parinaz
Malaria
Plasmodium vivax
Adherence
Primaquine
Rate of recurrence
Supervision
title_short Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
title_full Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
title_fullStr Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
title_full_unstemmed Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
title_sort Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis
dc.creator.none.fl_str_mv Mehdipour, Parinaz
Rajasekhar, Megha
Dini, Saber
Zaloumis, Sophie
Abreha, Tesfay
Adam, Ishag
Awab, Ghulam Rahim
Baird, J. Kevin
Brasil, Larissa Wanderley
Chu, Cindy S.
Cui, Liwang
Daher, André Bastos
Gomes, Margarete do Socorro Mendonça
Gonzalez Ceron, Lilia
Hwang, Jimee
Karunajeewa, Harin
Lacerda, Marcus Vinícius Guimarães de
Andrade, Simone Ladeia
Leslie, Toby
Ley, Benedikt
Lidia, Kartini
Llanos Cuentas, Alejandro
Longley, Rhea J.
Monteiro, Wuelton Marcelo
Pereira, Dhelio Batista
Rijal, Komal Raj
Saravu, Kavitha
Sutanto, Inge
Taylor, Walter R. J.
Thanh, Pham Vinh
Thriemer, Kamala
Vieira, José Luiz Fernandes
White, Nicholas J.
Zuluaga Idarraga, Lina M.
Guerin, Philippe J.
Price, Ric N.
Simpson, Julie A.
Commons, Robert J.
author Mehdipour, Parinaz
author_facet Mehdipour, Parinaz
Rajasekhar, Megha
Dini, Saber
Zaloumis, Sophie
Abreha, Tesfay
Adam, Ishag
Awab, Ghulam Rahim
Baird, J. Kevin
Brasil, Larissa Wanderley
Chu, Cindy S.
Cui, Liwang
Daher, André Bastos
Gomes, Margarete do Socorro Mendonça
Gonzalez Ceron, Lilia
Hwang, Jimee
Karunajeewa, Harin
Lacerda, Marcus Vinícius Guimarães de
Andrade, Simone Ladeia
Leslie, Toby
Ley, Benedikt
Lidia, Kartini
Llanos Cuentas, Alejandro
Longley, Rhea J.
Monteiro, Wuelton Marcelo
Pereira, Dhelio Batista
Rijal, Komal Raj
Saravu, Kavitha
Sutanto, Inge
Taylor, Walter R. J.
Thanh, Pham Vinh
Thriemer, Kamala
Vieira, José Luiz Fernandes
White, Nicholas J.
Zuluaga Idarraga, Lina M.
Guerin, Philippe J.
Price, Ric N.
Simpson, Julie A.
Commons, Robert J.
author_role author
author2 Rajasekhar, Megha
Dini, Saber
Zaloumis, Sophie
Abreha, Tesfay
Adam, Ishag
Awab, Ghulam Rahim
Baird, J. Kevin
Brasil, Larissa Wanderley
Chu, Cindy S.
Cui, Liwang
Daher, André Bastos
Gomes, Margarete do Socorro Mendonça
Gonzalez Ceron, Lilia
Hwang, Jimee
Karunajeewa, Harin
Lacerda, Marcus Vinícius Guimarães de
Andrade, Simone Ladeia
Leslie, Toby
Ley, Benedikt
Lidia, Kartini
Llanos Cuentas, Alejandro
Longley, Rhea J.
Monteiro, Wuelton Marcelo
Pereira, Dhelio Batista
Rijal, Komal Raj
Saravu, Kavitha
Sutanto, Inge
Taylor, Walter R. J.
Thanh, Pham Vinh
Thriemer, Kamala
Vieira, José Luiz Fernandes
White, Nicholas J.
Zuluaga Idarraga, Lina M.
Guerin, Philippe J.
Price, Ric N.
Simpson, Julie A.
Commons, Robert J.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.en.none.fl_str_mv Malaria
Plasmodium vivax
Adherence
Primaquine
Rate of recurrence
Supervision
topic Malaria
Plasmodium vivax
Adherence
Primaquine
Rate of recurrence
Supervision
description Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
publishDate 2023
dc.date.issued.fl_str_mv 2023
dc.date.accessioned.fl_str_mv 2024-03-15T11:27:44Z
dc.date.available.fl_str_mv 2024-03-15T11:27:44Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv MEHDIPOUR, Parinaz et al. Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis. Malaria Journal, v. 22, n. 306, p. 1-14, 10 Oct. 2023.
dc.identifier.uri.fl_str_mv https://arca.fiocruz.br/handle/icict/63076
dc.identifier.issn.none.fl_str_mv 1475-2875
dc.identifier.doi.none.fl_str_mv 10.1186/s12936-023-04725-w
dc.identifier.eissn.none.fl_str_mv 1475-2875
identifier_str_mv MEHDIPOUR, Parinaz et al. Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis. Malaria Journal, v. 22, n. 306, p. 1-14, 10 Oct. 2023.
1475-2875
10.1186/s12936-023-04725-w
url https://arca.fiocruz.br/handle/icict/63076
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
bitstream.url.fl_str_mv https://arca.fiocruz.br/bitstreams/42fd3452-a30d-45e1-8f4d-fca318aa2794/download
https://arca.fiocruz.br/bitstreams/624ad233-ab6a-4886-8ded-8d15de63d216/download
https://arca.fiocruz.br/bitstreams/53b0cb71-ecdf-47e9-9a46-b8005feccda9/download
https://arca.fiocruz.br/bitstreams/d2e91003-cd0c-4f5a-b3e7-861d7d14cd32/download
bitstream.checksum.fl_str_mv 5a560609d32a3863062d77ff32785d58
dccc858ba250076f7e91d84a3d04749c
f06868fa5bf664d829832e56d9967a4b
6c0392410101810214eebd84be4e9e48
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)
repository.mail.fl_str_mv repositorio.arca@fiocruz.br
_version_ 1853674334433837056
spelling 2024-03-15T11:27:44Z2024-03-15T11:27:44Z2023MEHDIPOUR, Parinaz et al. Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysis. Malaria Journal, v. 22, n. 306, p. 1-14, 10 Oct. 2023.1475-2875https://arca.fiocruz.br/handle/icict/6307610.1186/s12936-023-04725-w1475-2875Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.Robert J. Commons, Julie A. Simpson and Ric N. Price are supported by Australian National Health and Medical Research Council (NHMRC) Investigator Grants (1194702, 1196068, 2008501).This work is supported by the Wellcome Trust (grant 089179 to Cindy S. Chu, FN and Nicholas J. White).Nicholas J. White is a Wellcome Trust Principal Fellow (093956/Z/10/C).Jimee Hwang receives salary support from the U.S. President's Malaria Initiative.Marcus Vinícius Guimarães de Lacerda is a fellow from the National Council for Scientifc and Technological Development (CNPq).This research was supported by a grant from Australian NHMRC for the Australian Centre for Research Excellence in Malaria Elimination (1134989).This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation INV-024389.The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, Australia.The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, Australia.The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, Australia.The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, Australia.Columbia University Mailman School of Public Health. International Center for AIDS Care and Treatment Programs (ICAP). Addis Ababa, Ethiopia.Qassim University. Unaizah College of Medicine and Medical Sciences. Department of Obstetrics and Gynecology. Unaizah, Saudi Arabia.Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand / Nangarhar University. Nangarhar Medical Faculty. Jalalabad, Afghanistan.Universitas Indonesia. Faculty of Medicine. Oxford University Clinical Research Unit Indonesia. Jakarta, Indonesia / Oxford University. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Diretoria de Ensino e Pesquisa. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, Brasil.Oxford University. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit. Shoklo Malaria Research Unit. Mae Sot, Thailand.University of South Florida. Morsani College of Medicine. Department of Internal Medicine. Tampa, FL, USA.Fundação Oswaldo Cruz. Presidência. Vice Presidência de Pesquisa e Coleções Biológicas. Rio de Janeiro, RJ, Brasil.Superintendência de Vigilância em Saúde. Macapá, AP, Brasil / Universidade Federal do Amapá. Macapá, AP, Brasil.National Institute for Public Health. Regional Centre for Public Health Research. Tapachula, Chiapas, Mexico.U.S. Centers for Disease Control and Prevention. Malaria Branch. U.S. President's Malaria Initiative. Atlanta, GA, USA / University of California San Francisco. Global Health Group. San Francisco, USA.The University of Melbourne. Melbourne Medical School. Department of Medicine-Western Health. St. Albans, VIC, Australia.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil / University of Texas Medical Branch. Galveston, TX, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Doenças Parasitárias. Rio de Janeiro, RJ, Brasil / Nova University of Lisbon. Institute of Hygiene and Tropical Medicine. Global Health and Tropical Medicine. Lisbon, Portugal.London School of Hygiene and Tropical Medicine. Department of Infectious and Tropical Diseases. London, UK / HealthNet-TPO. Kabul, Afghanistan.Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia.Universitas Nusa Cendana. Faculty of Medicine and Veterinary Medicine. Department of Pharmacology and Therapy. Kupang, Indonesia.Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical “Alexander Von Humboldt”. Unit of Leishmaniasis and Malaria. Lima, Peru.Mahidol University. Faculty of Tropical Medicine. Mahidol Vivax Research Unit. Bangkok, Thailand / Walter and Eliza Hall Institute of Medical Research. Population Health and Immunity Division. Melbourne, Australia / University of Melbourne. Department of Medical Biology. Melbourne, Australia.Universidade do Estado do Amazonas. Manaus, AM, Brasil.Centro de Pesquisa em Medicina Tropical. Porto Velho, RO, Brasil / Universidade Federal de Rondônia. Porto Velho, RO, Brasil.Tribhuvan University. Central Department of Microbiology. Kirtipur, Kathmandu, Nepal / Mahidol University. Faculty of Tropical Medicine. Department of Clinical Tropical Medicine. Bangkok, Thailand.Manipal Academy of Higher Education. Kasturba Medical College Manipal. Department of Infectious Diseases. Madhava Nagar, Manipal, Karnataka, India / Manipal Academy of Higher Education. Prasanna School of Public Health. Manipal Centre for Infectious Diseases. Madhava Nagar, Manipal, Karnataka, India.University of Indonesia. Faculty of Medicine. Department of Parasitology. Jakarta, Indonesia.Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand / Oxford University. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.National Institute of Malariology, Parasitology and Entomology. Hanoi, Vietnam.Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia.Universidade Federal do Pará. Belém, PA, Brasil.Mahidol University. Faculty of Tropical Medicine. Mahidol Oxford Tropical Medicine Research Unit (MORU). Bangkok, Thailand / Oxford University. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK.Universidad de Antioquia. Facultad de Medicina. Grupo Malaria. Medellín, Colombia / Universidad de Antioquia. Facultad Nacional de Salud Publica. Medellín, Colombia.Oxford University. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / WorldWide Antimalarial Resistance Network (WWARN). Oxford, UK / Infectious Diseases Data Observatory (IDDO). Oxford, UK.Oxford University. Nuffield Department of Medicine. Centre for Tropical Medicine and Global Health. Oxford, UK / Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Darwin, NT, Australia.The University of Melbourne. Melbourne School of Population and Global Health. Centre for Epidemiology and Biostatistics. Melbourne, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Darwin, NT, Australia.Charles Darwin University. Menzies School of Health Research. Global Health Division. Darwin, NT, Australia / WorldWide Antimalarial Resistance Network (WWARN). Asia-Pacific Regional Centre. Darwin, NT, Australia / Grampians Health – Ballarat. General and Subspecialty Medicine. Ballarat, Australia.Background: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. Methods: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. Results: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1–16.1] in patients with poor adherence compared to 5.8% [5.0–6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8–2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3–15.2] in patients with poor adherence and 4.9% [4.1–5.8] in patients with full adherence; p < 0.001. Conclusion: Reduced adherence, including less supervision, increases the risk of vivax recurrence.engBMCEffect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a worldwide antimalarial resistance network systematic review and individual patient data meta-analysisinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleMalariaPlasmodium vivaxAdherencePrimaquineRate of recurrenceSupervisioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZMehdipour, ParinazRajasekhar, MeghaDini, SaberZaloumis, SophieAbreha, TesfayAdam, IshagAwab, Ghulam RahimBaird, J. KevinBrasil, Larissa WanderleyChu, Cindy S.Cui, LiwangDaher, André BastosGomes, Margarete do Socorro MendonçaGonzalez Ceron, LiliaHwang, JimeeKarunajeewa, HarinLacerda, Marcus Vinícius Guimarães deAndrade, Simone LadeiaLeslie, TobyLey, BenediktLidia, KartiniLlanos Cuentas, AlejandroLongley, Rhea J.Monteiro, Wuelton MarceloPereira, Dhelio BatistaRijal, Komal RajSaravu, KavithaSutanto, IngeTaylor, Walter R. J.Thanh, Pham VinhThriemer, KamalaVieira, José Luiz FernandesWhite, Nicholas J.Zuluaga Idarraga, Lina M.Guerin, Philippe J.Price, Ric N.Simpson, Julie A.Commons, Robert J.LICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://arca.fiocruz.br/bitstreams/42fd3452-a30d-45e1-8f4d-fca318aa2794/download5a560609d32a3863062d77ff32785d58MD51falseAnonymousREADORIGINALve_Andre_Daher_etal_VPPCB_2023.pdfve_Andre_Daher_etal_VPPCB_2023.pdfapplication/pdf1155920https://arca.fiocruz.br/bitstreams/624ad233-ab6a-4886-8ded-8d15de63d216/downloaddccc858ba250076f7e91d84a3d04749cMD52trueAnonymousREADTEXTve_Andre_Daher_etal_VPPCB_2023.pdf.txtve_Andre_Daher_etal_VPPCB_2023.pdf.txtExtracted texttext/plain72995https://arca.fiocruz.br/bitstreams/53b0cb71-ecdf-47e9-9a46-b8005feccda9/downloadf06868fa5bf664d829832e56d9967a4bMD513falseAnonymousREADTHUMBNAILve_Andre_Daher_etal_VPPCB_2023.pdf.jpgve_Andre_Daher_etal_VPPCB_2023.pdf.jpgGenerated Thumbnailimage/jpeg40170https://arca.fiocruz.br/bitstreams/d2e91003-cd0c-4f5a-b3e7-861d7d14cd32/download6c0392410101810214eebd84be4e9e48MD514falseAnonymousREADicict/630762025-12-10 12:21:44.605open.accessoai:arca.fiocruz.br:icict/63076https://arca.fiocruz.brRepositório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352025-12-10T15:21:44Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)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
score 15,300719