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 journalArticle

10 Citations (Scopus)

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 - 01-09-2018

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Primaquine
Plasmodium vivax
Chloroquine
Antimalarials
Meta-Analysis
Recurrence
Vivax Malaria
Treatment Failure
MEDLINE
Biomedical Research
Regression Analysis
Research Personnel
Clinical Trials
Databases

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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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.
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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",
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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 journalArticle

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.

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

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