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.

Pham Vinh Thanh, Kartini Lidia, Alejandro Llanos-Cuentas, Rhea J Longley, Wuelton Marcelo Monteiro, Dhelio B Pereira, Komal Raj Rijal, Kavitha Saravu, Inge Sutanto, Walter R J Taylor, Benedikt Ley, Kamala Thriemer, José Luiz F Vieira, Nicholas J White, Lina M Zuluaga-Idarraga, Philippe J Guerin, Ric N Price, Julie A Simpson, Robert J Commons, Liwang Cui, Megha Rajasekhar, Saber Dini, Sophie Zaloumis, Tesfay Abreha, Ishag Adam, Ghulam Rahim Awab, J Kevin Baird, Larissa W Brasil, Cindy S Chu, Parinaz Mehdipour, André Daher, Margarete do Socorro M Gomes, Lilia Gonzalez-Ceron, Jimee Hwang, Harin Karunajeewa, Marcus V G Lacerda, Simone Ladeia-Andrade, Toby Leslie

Journal: Malaria journal 2023;22(1):306

PMID: 37817240

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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.

Address: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.; ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia.; Department of Obstetrics and Gynecology, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia.; Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Nangarhar Medical Faculty, Nangarhar University, Jalalabad, Afghanistan.; Oxford University Clinical Research Unit Indonesia, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK.; Diretoria de Ensino E Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, AM, Brazil.; Programa de Pós‑Graduação em Medicina Tropical, Universidade Do Estado Do Amazonas, Manaus, AM, Brazil.; Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.; Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.; Fiocruz Clinical Research Platform, Vice-Presidency of Research and Biological Collections, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.; Superintendência de Vigilância Em Saúde Do Estado Do Amapá - SVS/AP, Macapá, Amapá, Brazil.; Federal University of aMAPA, Universidade Federal Do Amapá - UNIFAP), Macapá, Amapá, Brazil.; Regional Centre for Public Health Research, National Institute for Public Health, Tapachula, Chiapas, Mexico.; U.S. President's Malaria Initiative, Malaria Branch, U.S. Centers for Disease Control and Prevention, Atlanta, GA, USA.; Global Health Group, University of California San Francisco, San Francisco, USA.; Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, St. Albans, VIC, Australia.; Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil.; Instituto Leônidas & Maria Deane, Fiocruz, Manaus, Brazil.; University of Texas Medical Branch, Galveston, USA.; Laboratory of Parasitic Diseases, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.; Global Health and Tropical Medicine, Institute of Hygiene and Tropical Medicine, Nova University of Lisbon, Lisbon, Portugal.; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; HealthNet-TPO, Kabul, Afghanistan.; Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.; Department of Pharmacology and Therapy, Faculty of Medicine and Veterinary Medicine, Universitas Nusa Cendana, Kupang, Indonesia.; Unit of Leishmaniasis and Malaria, Instituto de Medicina Tropical "Alexander Von Humboldt", Universidad Peruana Cayetano Heredia, Lima, Peru.; Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.; Department of Medical Biology, University of Melbourne, Melbourne, Australia.; Universidade Do Estado Do Amazonas, Manaus, Brazil.; Centro de Pesquisa Em Medicina Tropical de Rondonia (CEPEM), Porto Velho, Brazil.; Fundação Universidade Federal de Rondonia (UNIR), Porto Velho, Brazil.; Central Department of Microbiology, Tribhuvan University, Kirtipur, Kathmandu, Nepal.; Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.; Department of Infectious Diseases, Kasturba Medical College Manipal, Manipal Academy of Higher Education, Madhava Nagar, Manipal, Karnataka, India.; Manipal Centre for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Madhava Nagar, Manipal, Karnataka, India.; Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia.; National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.; Federal University of Pará, Universidade Federal Do Pará - UFPA), Belém, Pará, Brazil.; Grupo Malaria, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.; Facultad Nacional de Salud Publica, Universidad de Antioquia, Medellín, Colombia.; WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.; Infectious Diseases Data Observatory (IDDO), Oxford, UK.; WorldWide Antimalarial Resistance Network (WWARN), Asia-Pacific Regional Centre, Darwin, NT, Australia.; Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia. [email protected].; WorldWide Antimalarial Resistance Network (WWARN), Asia-Pacific Regional Centre, Darwin, NT, Australia. [email protected].; General and Subspecialty Medicine, Grampians Health - Ballarat, Ballarat, Australia. [email protected].

DOI: 10.1186/s12936-023-04725-w

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MeSH Terms: Humans, Primaquine, Antimalarials, Plasmodium vivax, Recurrence, Malaria, Vivax, Folic Acid Antagonists