TY - JOUR
T1 - Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence
T2 - a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis
AU - Mehdipour, Parinaz
AU - Rajasekhar, Megha
AU - Dini, Saber
AU - Zaloumis, Sophie
AU - Abreha, Tesfay
AU - Adam, Ishag
AU - Awab, Ghulam Rahim
AU - Baird, J. Kevin
AU - Brasil, Larissa W.
AU - Chu, Cindy S.
AU - Cui, Liwang
AU - Daher, André
AU - do Socorro M Gomes, Margarete
AU - Gonzalez‑Ceron, Lilia
AU - Hwang, Jimee
AU - Karunajeewa, Harin
AU - Lacerda, Marcus V.G.
AU - Ladeia-Andrade, Simone
AU - Leslie, Toby
AU - Ley, Benedikt
AU - Lidia, Kartini
AU - Llanos-Cuentas, Alejandro
AU - Longley, Rhea J.
AU - Monteiro, Wuelton Marcelo
AU - Pereira, Dhelio B.
AU - Rijal, Komal Raj
AU - Saravu, Kavitha
AU - Sutanto, Inge
AU - Taylor, Walter R.J.
AU - Thanh, Pham Vinh
AU - Thriemer, Kamala
AU - Vieira, José Luiz F.
AU - White, Nicholas J.
AU - Zuluaga-Idarraga, Lina M.
AU - Guerin, Philippe J.
AU - Price, Ric N.
AU - Simpson, Julie A.
AU - Commons, Robert J.
N1 - Funding Information:
We thank all patients and staff who participated in these clinical trials at all the sites, and the WWARN team for technical and administrative support. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the United States Centers for Disease Control and Prevention. Bipin Adhikari (Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK). Mohammad Shafiul Alam (International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh). Ashenafi Assefa (Malaria and Other Parasitic Disease Research Team, Ethiopian Public Health Institute, Addis Ababa, Ethiopia; Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, USA). Sarah C. Boyd (Royal Brisbane and Women's Hospital, Brisbane, Australia). Nguyen Hoang Chau (Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam). Nicholas P.J. Day (Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand). Tamiru Shibiru Degaga (Arbaminch University College of Medicine & Health Sciences, Arbaminch, Ethiopia). Arjen M. Dondorp (Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK). Annette Erhart (Disease Control and Elimination Theme, Medical Research Council Unit, Fajara, The Gambia; Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium). Marcelo U. Ferreira (Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Global Health and Tropical Medicine, Institute of Hygiene and Tropical Medicine, NOVA University of Lisbon, Lisbon, Portugal). Prakash Ghimire (Central Department of Microbiology, Tribhuvan University, Kirtipur, Kathmandu, Nepal). Justin A. Green (Formerly Senior Director, Global Health, GlaxoSmithKline, Brentford, UK). Wasif Ali Khan (International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh). Gavin C. K. W. Koh (Department of Infectious Diseases, Northwick Park Hospital, Harrow, UK). Asrat Hailu Mekuria (Addis Ababa University, College of Health Sciences, Addis Ababa, Ethiopia; Arbaminch University, Arbaminch, Ethiopia; University of Gondar, Gondar, Ethiopia). Ivo Mueller (Population Health and Immunity Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia). Mohammad Nader Naadim (Health Protection and Research Organisation, Kabul, Afghanistan). Erni J. Nelwan (Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Division of Tropical Medicine and Infectious Disease, Department of Internal Medicine, Cipto Mangunkusumo Hospital, Jakarta, Indonesia). Francois Nosten (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, UK). Ayodhia Pitaloka Pasaribu (Department of Pediatrics, Medical Faculty, Universitas Sumatera Utara, Medan, North Sumatera, Indonesia). Sasithon Pukrittayakamee (Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand). Mark Rowland (Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK). Jetsumon Sattabongkot (Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol). Kasia Stepniewska (Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK; Infectious Diseases Data Observatory (IDDO), Oxford, UK). Guilherme Suarez‑Kurtz (Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil; Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil). Lorenz von Seidlein (Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK). Charles J. Woodrow (Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand). Adugna Woyessa (Ethiopian Public Health Institute, Addis Ababa, Ethiopia).
Funding Information:
RJC, JAS and RNP 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 CSC, FN and NJW). NJW is a Wellcome Trust Principal Fellow (093956/Z/10/C). JH receives salary support from the U.S. President’s Malaria Initiative. MVGL is a fellow from the National Council for Scientific 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. 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.
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Adherence
KW - Malaria
KW - Plasmodium vivax
KW - Primaquine
KW - Rate of recurrence
KW - Supervision
UR - http://www.scopus.com/inward/record.url?scp=85173698545&partnerID=8YFLogxK
U2 - 10.1186/s12936-023-04725-w
DO - 10.1186/s12936-023-04725-w
M3 - Article
C2 - 37817240
AN - SCOPUS:85173698545
SN - 1475-2875
VL - 22
JO - Malaria Journal
JF - Malaria Journal
IS - 1
M1 - 306
ER -
