The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine

a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

Robert J. Commons, Julie A. Simpson, Kamala Thriemer, Cindy S. Chu, Nicholas M. Douglas, Tesfay Abreha, Sisay G. Alemu, Arletta Añez, Nicholas M. Anstey, Abraham Aseffa, Ashenafi Assefa, Ghulam R. Awab, J. Kevin Baird, Bridget E. Barber, Isabelle Borghini-Fuhrer, Umberto D'Alessandro, Prabin Dahal, André Daher, Peter J. de Vries, Annette Erhart & 32 others Margarete S.M. Gomes, Matthew J. Grigg, Jimee Hwang, Piet A. Kager, Tsige Ketema, Wasif A. Khan, Marcus V.G. Lacerda, Toby Leslie, Benedikt Ley, Kartini Lidia, Wuelton M. Monteiro, Dhelio B. Pereira, Giao T. Phan, Aung P. Phyo, Mark Rowland, Kavitha Saravu, Carol H. Sibley, André M. Siqueira, Kasia Stepniewska, Walter R.J. Taylor, Guy Thwaites, Binh Q. Tran, Tran T. Hien, José Luiz F. Vieira, Sonam Wangchuk, James Watson, Timothy William, Charles J. Woodrow, Francois Nosten, Philippe J. Guerin, Nicholas J. White, Ric N. Price

    Research output: Contribution to journalArticleResearchpeer-review

    4 Downloads (Pure)

    Abstract

    Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.

    Methods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model.

    Results: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL.

    Conclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.

    Trial Registration: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

    Original languageEnglish
    Article number151
    Pages (from-to)1-13
    Number of pages13
    JournalBMC Medicine
    Volume17
    DOIs
    Publication statusPublished - 1 Aug 2019

    Fingerprint

    Primaquine
    Vivax Malaria
    Chloroquine
    Antimalarials
    Meta-Analysis
    Hemoglobins
    Malaria
    Glucosephosphate Dehydrogenase Deficiency
    Plasmodium vivax
    Therapeutics
    Nonlinear Dynamics
    Parasitemia
    Glucosephosphate Dehydrogenase
    Hemolysis
    Anemia
    Pharmaceutical Preparations

    Cite this

    Commons, Robert J. ; Simpson, Julie A. ; Thriemer, Kamala ; Chu, Cindy S. ; Douglas, Nicholas M. ; Abreha, Tesfay ; Alemu, Sisay G. ; Añez, Arletta ; Anstey, Nicholas M. ; Aseffa, Abraham ; Assefa, Ashenafi ; Awab, Ghulam R. ; Baird, J. Kevin ; Barber, Bridget E. ; Borghini-Fuhrer, Isabelle ; D'Alessandro, Umberto ; Dahal, Prabin ; Daher, André ; de Vries, Peter J. ; Erhart, Annette ; Gomes, Margarete S.M. ; Grigg, Matthew J. ; Hwang, Jimee ; Kager, Piet A. ; Ketema, Tsige ; Khan, Wasif A. ; Lacerda, Marcus V.G. ; Leslie, Toby ; Ley, Benedikt ; Lidia, Kartini ; Monteiro, Wuelton M. ; Pereira, Dhelio B. ; Phan, Giao T. ; Phyo, Aung P. ; Rowland, Mark ; Saravu, Kavitha ; Sibley, Carol H. ; Siqueira, André M. ; Stepniewska, Kasia ; Taylor, Walter R.J. ; Thwaites, Guy ; Tran, Binh Q. ; Hien, Tran T. ; Vieira, José Luiz F. ; Wangchuk, Sonam ; Watson, James ; William, Timothy ; Woodrow, Charles J. ; Nosten, Francois ; Guerin, Philippe J. ; White, Nicholas J. ; Price, Ric N. / The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine : a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis. In: BMC Medicine. 2019 ; Vol. 17. pp. 1-13.
    @article{cb7a55bc86cc4002a73bafb97e88871b,
    title = "The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis",
    abstract = "Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. Methods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. Results: In total, 3421 patients from 29 studies were included: 1692 (49.5{\%}) with normal G6PD status, 1701 (49.7{\%}) with unknown status and 28 (0.8{\%}) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95{\%} CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3{\%} (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25{\%} to < 7 g/dL) and a 1{\%} (4/389) risk of a fall in haemoglobin > 5 g/dL. Conclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. Trial Registration: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.",
    keywords = "Chloroquine, Haemoglobin, Haemolysis, Plasmodium vivax, Pooled analysis, Primaquine",
    author = "Commons, {Robert J.} and Simpson, {Julie A.} and Kamala Thriemer and Chu, {Cindy S.} and Douglas, {Nicholas M.} and Tesfay Abreha and Alemu, {Sisay G.} and Arletta A{\~n}ez and Anstey, {Nicholas M.} and Abraham Aseffa and Ashenafi Assefa and Awab, {Ghulam R.} and Baird, {J. Kevin} and Barber, {Bridget E.} and Isabelle Borghini-Fuhrer and Umberto D'Alessandro and Prabin Dahal and Andr{\'e} Daher and {de Vries}, {Peter J.} and Annette Erhart and Gomes, {Margarete S.M.} and Grigg, {Matthew J.} and Jimee Hwang and Kager, {Piet A.} and Tsige Ketema and Khan, {Wasif A.} and Lacerda, {Marcus V.G.} and Toby Leslie and Benedikt Ley and Kartini Lidia and Monteiro, {Wuelton M.} and Pereira, {Dhelio B.} and Phan, {Giao T.} and Phyo, {Aung P.} and Mark Rowland and Kavitha Saravu and Sibley, {Carol H.} and Siqueira, {Andr{\'e} M.} and Kasia Stepniewska and Taylor, {Walter R.J.} and Guy Thwaites and Tran, {Binh Q.} and Hien, {Tran T.} and Vieira, {Jos{\'e} Luiz F.} and Sonam Wangchuk and James Watson and Timothy William and Woodrow, {Charles J.} and Francois Nosten and Guerin, {Philippe J.} and White, {Nicholas J.} and Price, {Ric N.}",
    year = "2019",
    month = "8",
    day = "1",
    doi = "10.1186/s12916-019-1386-6",
    language = "English",
    volume = "17",
    pages = "1--13",
    journal = "BMC Medicine",
    issn = "1741-7015",
    publisher = "BioMed Central",

    }

    Commons, RJ, Simpson, JA, Thriemer, K, Chu, CS, Douglas, NM, Abreha, T, Alemu, SG, Añez, A, Anstey, NM, Aseffa, A, Assefa, A, Awab, GR, Baird, JK, Barber, BE, Borghini-Fuhrer, I, D'Alessandro, U, Dahal, P, Daher, A, de Vries, PJ, Erhart, A, Gomes, MSM, Grigg, MJ, Hwang, J, Kager, PA, Ketema, T, Khan, WA, Lacerda, MVG, Leslie, T, Ley, B, Lidia, K, Monteiro, WM, Pereira, DB, Phan, GT, Phyo, AP, Rowland, M, Saravu, K, Sibley, CH, Siqueira, AM, Stepniewska, K, Taylor, WRJ, Thwaites, G, Tran, BQ, Hien, TT, Vieira, JLF, Wangchuk, S, Watson, J, William, T, Woodrow, CJ, Nosten, F, Guerin, PJ, White, NJ & Price, RN 2019, 'The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis', BMC Medicine, vol. 17, 151, pp. 1-13. https://doi.org/10.1186/s12916-019-1386-6

    The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine : a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis. / Commons, Robert J.; Simpson, Julie A.; Thriemer, Kamala; Chu, Cindy S.; Douglas, Nicholas M.; Abreha, Tesfay; Alemu, Sisay G.; Añez, Arletta; Anstey, Nicholas M.; Aseffa, Abraham; Assefa, Ashenafi; Awab, Ghulam R.; Baird, J. Kevin; Barber, Bridget E.; Borghini-Fuhrer, Isabelle; D'Alessandro, Umberto; Dahal, Prabin; Daher, André; de Vries, Peter J.; Erhart, Annette; Gomes, Margarete S.M.; Grigg, Matthew J.; Hwang, Jimee; Kager, Piet A.; Ketema, Tsige; Khan, Wasif A.; Lacerda, Marcus V.G.; Leslie, Toby; Ley, Benedikt; Lidia, Kartini; Monteiro, Wuelton M.; Pereira, Dhelio B.; Phan, Giao T.; Phyo, Aung P.; Rowland, Mark; Saravu, Kavitha; Sibley, Carol H.; Siqueira, André M.; Stepniewska, Kasia; Taylor, Walter R.J.; Thwaites, Guy; Tran, Binh Q.; Hien, Tran T.; Vieira, José Luiz F.; Wangchuk, Sonam; Watson, James; William, Timothy; Woodrow, Charles J.; Nosten, Francois; Guerin, Philippe J.; White, Nicholas J.; Price, Ric N.

    In: BMC Medicine, Vol. 17, 151, 01.08.2019, p. 1-13.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine

    T2 - a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

    AU - Commons, Robert J.

    AU - Simpson, Julie A.

    AU - Thriemer, Kamala

    AU - Chu, Cindy S.

    AU - Douglas, Nicholas M.

    AU - Abreha, Tesfay

    AU - Alemu, Sisay G.

    AU - Añez, Arletta

    AU - Anstey, Nicholas M.

    AU - Aseffa, Abraham

    AU - Assefa, Ashenafi

    AU - Awab, Ghulam R.

    AU - Baird, J. Kevin

    AU - Barber, Bridget E.

    AU - Borghini-Fuhrer, Isabelle

    AU - D'Alessandro, Umberto

    AU - Dahal, Prabin

    AU - Daher, André

    AU - de Vries, Peter J.

    AU - Erhart, Annette

    AU - Gomes, Margarete S.M.

    AU - Grigg, Matthew J.

    AU - Hwang, Jimee

    AU - Kager, Piet A.

    AU - Ketema, Tsige

    AU - Khan, Wasif A.

    AU - Lacerda, Marcus V.G.

    AU - Leslie, Toby

    AU - Ley, Benedikt

    AU - Lidia, Kartini

    AU - Monteiro, Wuelton M.

    AU - Pereira, Dhelio B.

    AU - Phan, Giao T.

    AU - Phyo, Aung P.

    AU - Rowland, Mark

    AU - Saravu, Kavitha

    AU - Sibley, Carol H.

    AU - Siqueira, André M.

    AU - Stepniewska, Kasia

    AU - Taylor, Walter R.J.

    AU - Thwaites, Guy

    AU - Tran, Binh Q.

    AU - Hien, Tran T.

    AU - Vieira, José Luiz F.

    AU - Wangchuk, Sonam

    AU - Watson, James

    AU - William, Timothy

    AU - Woodrow, Charles J.

    AU - Nosten, Francois

    AU - Guerin, Philippe J.

    AU - White, Nicholas J.

    AU - Price, Ric N.

    PY - 2019/8/1

    Y1 - 2019/8/1

    N2 - Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. Methods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. Results: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. Conclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. Trial Registration: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

    AB - Background: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. Methods: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. Results: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. Conclusions: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. Trial Registration: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

    KW - Chloroquine

    KW - Haemoglobin

    KW - Haemolysis

    KW - Plasmodium vivax

    KW - Pooled analysis

    KW - Primaquine

    UR - http://www.scopus.com/inward/record.url?scp=85070892819&partnerID=8YFLogxK

    U2 - 10.1186/s12916-019-1386-6

    DO - 10.1186/s12916-019-1386-6

    M3 - Article

    VL - 17

    SP - 1

    EP - 13

    JO - BMC Medicine

    JF - BMC Medicine

    SN - 1741-7015

    M1 - 151

    ER -