The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence

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

Robert J. Commons, Julie A. Simpson, Kamala Thriemer, Georgina S. Humphreys, Tesfay Abreha, Sisay G. Alemu, Arletta Añez, Nicholas M. Anstey, Ghulam R. Awab, J. Kevin Baird, Bridget E. Barber, Isabelle Borghini-Fuhrer, Cindy S. Chu, Umberto D'Alessandro, Prabin Dahal, André Daher, Peter J. de Vries, Annette Erhart, Margarete S.M. Gomes, Lilia Gonzalez-Ceron & 34 others Matthew J. Grigg, Aliehsan Heidari, Jimee Hwang, Piet A. Kager, Tsige Ketema, Wasif A. Khan, Marcus V.G. Lacerda, Toby Leslie, Benedikt Ley, Kartini Lidia, Wuelton M. Monteiro, Francois Nosten, Dhelio B. Pereira, Giao T. Phan, Aung P. Phyo, Mark Rowland, Kavitha Saravu, Carol H. Sibley, André M. Siqueira, Kasia Stepniewska, Inge Sutanto, Walter R.J. Taylor, Guy Thwaites, Binh Q. Tran, Hien T. Tran, Neena Valecha, José Luiz F. Vieira, Sonam Wangchuk, Timothy William, Charles J. Woodrow, Lina Zuluaga-Idarraga, Philippe J. Guerin, Nicholas J. White, Ric N. Price

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings.

    Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310.

    Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001).

    Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

    Original languageEnglish
    Pages (from-to)1025-1034
    Number of pages10
    JournalThe Lancet Infectious Diseases
    Volume18
    Issue number9
    DOIs
    Publication statusPublished - 1 Sep 2018

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    Primaquine
    Plasmodium vivax
    Chloroquine
    Antimalarials
    Meta-Analysis
    Recurrence
    Vivax Malaria
    Treatment Failure
    MEDLINE
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    Cite this

    Commons, Robert J. ; Simpson, Julie A. ; Thriemer, Kamala ; Humphreys, Georgina S. ; Abreha, Tesfay ; Alemu, Sisay G. ; Añez, Arletta ; Anstey, Nicholas M. ; Awab, Ghulam R. ; Baird, J. Kevin ; Barber, Bridget E. ; Borghini-Fuhrer, Isabelle ; Chu, Cindy S. ; D'Alessandro, Umberto ; Dahal, Prabin ; Daher, André ; de Vries, Peter J. ; Erhart, Annette ; Gomes, Margarete S.M. ; Gonzalez-Ceron, Lilia ; Grigg, Matthew J. ; Heidari, Aliehsan ; Hwang, Jimee ; Kager, Piet A. ; Ketema, Tsige ; Khan, Wasif A. ; Lacerda, Marcus V.G. ; Leslie, Toby ; Ley, Benedikt ; Lidia, Kartini ; Monteiro, Wuelton M. ; Nosten, Francois ; Pereira, Dhelio B. ; Phan, Giao T. ; Phyo, Aung P. ; Rowland, Mark ; Saravu, Kavitha ; Sibley, Carol H. ; Siqueira, André M. ; Stepniewska, Kasia ; Sutanto, Inge ; Taylor, Walter R.J. ; Thwaites, Guy ; Tran, Binh Q. ; Tran, Hien T. ; Valecha, Neena ; Vieira, José Luiz F. ; Wangchuk, Sonam ; William, Timothy ; Woodrow, Charles J. ; Zuluaga-Idarraga, Lina ; Guerin, Philippe J. ; White, Nicholas J. ; Price, Ric N. / The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence : a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis. In: The Lancet Infectious Diseases. 2018 ; Vol. 18, No. 9. pp. 1025-1034.
    @article{9e0dabd8f9344a8ba8ec5591079878e6,
    title = "The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis",
    abstract = "Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8{\%}) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4{\%} (95{\%} CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95{\%} CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9{\%} (95{\%} CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001). Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.",
    author = "Commons, {Robert J.} and Simpson, {Julie A.} and Kamala Thriemer and Humphreys, {Georgina S.} and Tesfay Abreha and Alemu, {Sisay G.} and Arletta A{\~n}ez and Anstey, {Nicholas M.} and Awab, {Ghulam R.} and Baird, {J. Kevin} and Barber, {Bridget E.} and Isabelle Borghini-Fuhrer and Chu, {Cindy S.} 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 Lilia Gonzalez-Ceron and Grigg, {Matthew J.} and Aliehsan Heidari 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 Francois Nosten 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 Inge Sutanto and Taylor, {Walter R.J.} and Guy Thwaites and Tran, {Binh Q.} and Tran, {Hien T.} and Neena Valecha and Vieira, {Jos{\'e} Luiz F.} and Sonam Wangchuk and Timothy William and Woodrow, {Charles J.} and Lina Zuluaga-Idarraga and Guerin, {Philippe J.} and White, {Nicholas J.} and Price, {Ric N.}",
    year = "2018",
    month = "9",
    day = "1",
    doi = "10.1016/S1473-3099(18)30348-7",
    language = "English",
    volume = "18",
    pages = "1025--1034",
    journal = "The Lancet Infectious Diseases",
    issn = "1473-3099",
    publisher = "The Lancet Publishing Group",
    number = "9",

    }

    Commons, RJ, Simpson, JA, Thriemer, K, Humphreys, GS, Abreha, T, Alemu, SG, Añez, A, Anstey, NM, Awab, GR, Baird, JK, Barber, BE, Borghini-Fuhrer, I, Chu, CS, D'Alessandro, U, Dahal, P, Daher, A, de Vries, PJ, Erhart, A, Gomes, MSM, Gonzalez-Ceron, L, Grigg, MJ, Heidari, A, Hwang, J, Kager, PA, Ketema, T, Khan, WA, Lacerda, MVG, Leslie, T, Ley, B, Lidia, K, Monteiro, WM, Nosten, F, Pereira, DB, Phan, GT, Phyo, AP, Rowland, M, Saravu, K, Sibley, CH, Siqueira, AM, Stepniewska, K, Sutanto, I, Taylor, WRJ, Thwaites, G, Tran, BQ, Tran, HT, Valecha, N, Vieira, JLF, Wangchuk, S, William, T, Woodrow, CJ, Zuluaga-Idarraga, L, Guerin, PJ, White, NJ & Price, RN 2018, 'The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis', The Lancet Infectious Diseases, vol. 18, no. 9, pp. 1025-1034. https://doi.org/10.1016/S1473-3099(18)30348-7

    The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence : a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis. / Commons, Robert J.; Simpson, Julie A.; Thriemer, Kamala; Humphreys, Georgina S.; Abreha, Tesfay; Alemu, Sisay G.; Añez, Arletta; Anstey, Nicholas M.; Awab, Ghulam R.; Baird, J. Kevin; Barber, Bridget E.; Borghini-Fuhrer, Isabelle; Chu, Cindy S.; D'Alessandro, Umberto; Dahal, Prabin; Daher, André; de Vries, Peter J.; Erhart, Annette; Gomes, Margarete S.M.; Gonzalez-Ceron, Lilia; Grigg, Matthew J.; Heidari, Aliehsan; Hwang, Jimee; Kager, Piet A.; Ketema, Tsige; Khan, Wasif A.; Lacerda, Marcus V.G.; Leslie, Toby; Ley, Benedikt; Lidia, Kartini; Monteiro, Wuelton M.; Nosten, Francois; Pereira, Dhelio B.; Phan, Giao T.; Phyo, Aung P.; Rowland, Mark; Saravu, Kavitha; Sibley, Carol H.; Siqueira, André M.; Stepniewska, Kasia; Sutanto, Inge; Taylor, Walter R.J.; Thwaites, Guy; Tran, Binh Q.; Tran, Hien T.; Valecha, Neena; Vieira, José Luiz F.; Wangchuk, Sonam; William, Timothy; Woodrow, Charles J.; Zuluaga-Idarraga, Lina; Guerin, Philippe J.; White, Nicholas J.; Price, Ric N.

    In: The Lancet Infectious Diseases, Vol. 18, No. 9, 01.09.2018, p. 1025-1034.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence

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

    AU - Commons, Robert J.

    AU - Simpson, Julie A.

    AU - Thriemer, Kamala

    AU - Humphreys, Georgina S.

    AU - Abreha, Tesfay

    AU - Alemu, Sisay G.

    AU - Añez, Arletta

    AU - Anstey, Nicholas M.

    AU - Awab, Ghulam R.

    AU - Baird, J. Kevin

    AU - Barber, Bridget E.

    AU - Borghini-Fuhrer, Isabelle

    AU - Chu, Cindy S.

    AU - D'Alessandro, Umberto

    AU - Dahal, Prabin

    AU - Daher, André

    AU - de Vries, Peter J.

    AU - Erhart, Annette

    AU - Gomes, Margarete S.M.

    AU - Gonzalez-Ceron, Lilia

    AU - Grigg, Matthew J.

    AU - Heidari, Aliehsan

    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 - Nosten, Francois

    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 - Sutanto, Inge

    AU - Taylor, Walter R.J.

    AU - Thwaites, Guy

    AU - Tran, Binh Q.

    AU - Tran, Hien T.

    AU - Valecha, Neena

    AU - Vieira, José Luiz F.

    AU - Wangchuk, Sonam

    AU - William, Timothy

    AU - Woodrow, Charles J.

    AU - Zuluaga-Idarraga, Lina

    AU - Guerin, Philippe J.

    AU - White, Nicholas J.

    AU - Price, Ric N.

    PY - 2018/9/1

    Y1 - 2018/9/1

    N2 - Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001). Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

    AB - Background: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. Methods: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. Findings: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8–35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69–0·97; p=0·021) and in children younger than 5 years (0·59, 0·41–0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1–7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05–0·17; p<0·0001). Interpretation: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. Funding: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

    UR - http://www.scopus.com/inward/record.url?scp=85053837530&partnerID=8YFLogxK

    U2 - 10.1016/S1473-3099(18)30348-7

    DO - 10.1016/S1473-3099(18)30348-7

    M3 - Article

    VL - 18

    SP - 1025

    EP - 1034

    JO - The Lancet Infectious Diseases

    JF - The Lancet Infectious Diseases

    SN - 1473-3099

    IS - 9

    ER -