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https://www.arca.fiocruz.br/handle/icict/63076
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
Author
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.
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.
Affilliation
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.
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.
Abstract
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.
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