The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence

A systematic review and individual patient data meta-analysis

Robert J. Commons, Julie A. Simpson, Kamala Thriemer, Tesfay Abreha, Ishag Adam, Nicholas M. Anstey, Ashenafi Assefa, Ghulam R. Awab, J. Kevin Baird, Bridget E. Barber, Cindy S. Chu, Prabin Dahal, André Daher, Timothy M.E. Davis, Arjen M. Dondorp, Matthew J. Grigg, Georgina S. Humphreys, Jimee Hwang, Harin Karunajeewa, Moses Laman & 18 others Kartini Lidia, Brioni R. Moore, Ivo Mueller, Francois Nosten, Ayodhia P. Pasaribu, Dhelio B. Pereira, Aung P. Phyo, Jeanne R. Poespoprodjo, Carol H. Sibley, Kasia Stepniewska, Inge Sutanto, Guy Thwaites, Tran T. Hien, Nicholas J. White, Timothy William, Charles J. Woodrow, Philippe J. Guerin, Ric N. Price

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.

Methods and findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.

Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.
Original languageEnglish
Article numbere1002928
Pages (from-to)1-21
Number of pages21
JournalPLoS Medicine
Volume16
Issue number10
DOIs
Publication statusPublished - 4 Oct 2019

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dihydroartemisinin
Primaquine
Plasmodium vivax
Meta-Analysis
Recurrence
Confidence Intervals
Therapeutics
Hemoglobins
Vivax Malaria
artemether
piperaquine
lumefantrine
Chloroquine

Cite this

Commons, Robert J. ; Simpson, Julie A. ; Thriemer, Kamala ; Abreha, Tesfay ; Adam, Ishag ; Anstey, Nicholas M. ; Assefa, Ashenafi ; Awab, Ghulam R. ; Baird, J. Kevin ; Barber, Bridget E. ; Chu, Cindy S. ; Dahal, Prabin ; Daher, André ; Davis, Timothy M.E. ; Dondorp, Arjen M. ; Grigg, Matthew J. ; Humphreys, Georgina S. ; Hwang, Jimee ; Karunajeewa, Harin ; Laman, Moses ; Lidia, Kartini ; Moore, Brioni R. ; Mueller, Ivo ; Nosten, Francois ; Pasaribu, Ayodhia P. ; Pereira, Dhelio B. ; Phyo, Aung P. ; Poespoprodjo, Jeanne R. ; Sibley, Carol H. ; Stepniewska, Kasia ; Sutanto, Inge ; Thwaites, Guy ; Hien, Tran T. ; White, Nicholas J. ; William, Timothy ; Woodrow, Charles J. ; Guerin, Philippe J. ; Price, Ric N. / The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence : A systematic review and individual patient data meta-analysis. In: PLoS Medicine. 2019 ; Vol. 16, No. 10. pp. 1-21.
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title = "The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis",
abstract = "Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0{\%}, 95{\%} confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3{\%}, 95{\%} CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95{\%} CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95{\%} CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95{\%} CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95{\%} CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95{\%} CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95{\%} CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.",
author = "Commons, {Robert J.} and Simpson, {Julie A.} and Kamala Thriemer and Tesfay Abreha and Ishag Adam and Anstey, {Nicholas M.} and Ashenafi Assefa and Awab, {Ghulam R.} and Baird, {J. Kevin} and Barber, {Bridget E.} and Chu, {Cindy S.} and Prabin Dahal and Andr{\'e} Daher and Davis, {Timothy M.E.} and Dondorp, {Arjen M.} and Grigg, {Matthew J.} and Humphreys, {Georgina S.} and Jimee Hwang and Harin Karunajeewa and Moses Laman and Kartini Lidia and Moore, {Brioni R.} and Ivo Mueller and Francois Nosten and Pasaribu, {Ayodhia P.} and Pereira, {Dhelio B.} and Phyo, {Aung P.} and Poespoprodjo, {Jeanne R.} and Sibley, {Carol H.} and Kasia Stepniewska and Inge Sutanto and Guy Thwaites and Hien, {Tran T.} and White, {Nicholas J.} and Timothy William and Woodrow, {Charles J.} and Guerin, {Philippe J.} and Price, {Ric N.}",
year = "2019",
month = "10",
day = "4",
doi = "10.1371/journal.pmed.1002928",
language = "English",
volume = "16",
pages = "1--21",
journal = "PLoS Medicine",
issn = "1549-1277",
publisher = "Public Library of Science (PLoS)",
number = "10",

}

Commons, RJ, Simpson, JA, Thriemer, K, Abreha, T, Adam, I, Anstey, NM, Assefa, A, Awab, GR, Baird, JK, Barber, BE, Chu, CS, Dahal, P, Daher, A, Davis, TME, Dondorp, AM, Grigg, MJ, Humphreys, GS, Hwang, J, Karunajeewa, H, Laman, M, Lidia, K, Moore, BR, Mueller, I, Nosten, F, Pasaribu, AP, Pereira, DB, Phyo, AP, Poespoprodjo, JR, Sibley, CH, Stepniewska, K, Sutanto, I, Thwaites, G, Hien, TT, White, NJ, William, T, Woodrow, CJ, Guerin, PJ & Price, RN 2019, 'The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis', PLoS Medicine, vol. 16, no. 10, e1002928 , pp. 1-21. https://doi.org/10.1371/journal.pmed.1002928

The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence : A systematic review and individual patient data meta-analysis. / Commons, Robert J.; Simpson, Julie A.; Thriemer, Kamala; Abreha, Tesfay; Adam, Ishag; Anstey, Nicholas M.; Assefa, Ashenafi; Awab, Ghulam R.; Baird, J. Kevin; Barber, Bridget E.; Chu, Cindy S.; Dahal, Prabin; Daher, André; Davis, Timothy M.E.; Dondorp, Arjen M.; Grigg, Matthew J.; Humphreys, Georgina S.; Hwang, Jimee; Karunajeewa, Harin; Laman, Moses; Lidia, Kartini; Moore, Brioni R.; Mueller, Ivo; Nosten, Francois; Pasaribu, Ayodhia P.; Pereira, Dhelio B.; Phyo, Aung P.; Poespoprodjo, Jeanne R.; Sibley, Carol H.; Stepniewska, Kasia; Sutanto, Inge; Thwaites, Guy; Hien, Tran T.; White, Nicholas J.; William, Timothy; Woodrow, Charles J.; Guerin, Philippe J.; Price, Ric N.

In: PLoS Medicine, Vol. 16, No. 10, e1002928 , 04.10.2019, p. 1-21.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence

T2 - A systematic review and individual patient data meta-analysis

AU - Commons, Robert J.

AU - Simpson, Julie A.

AU - Thriemer, Kamala

AU - Abreha, Tesfay

AU - Adam, Ishag

AU - Anstey, Nicholas M.

AU - Assefa, Ashenafi

AU - Awab, Ghulam R.

AU - Baird, J. Kevin

AU - Barber, Bridget E.

AU - Chu, Cindy S.

AU - Dahal, Prabin

AU - Daher, André

AU - Davis, Timothy M.E.

AU - Dondorp, Arjen M.

AU - Grigg, Matthew J.

AU - Humphreys, Georgina S.

AU - Hwang, Jimee

AU - Karunajeewa, Harin

AU - Laman, Moses

AU - Lidia, Kartini

AU - Moore, Brioni R.

AU - Mueller, Ivo

AU - Nosten, Francois

AU - Pasaribu, Ayodhia P.

AU - Pereira, Dhelio B.

AU - Phyo, Aung P.

AU - Poespoprodjo, Jeanne R.

AU - Sibley, Carol H.

AU - Stepniewska, Kasia

AU - Sutanto, Inge

AU - Thwaites, Guy

AU - Hien, Tran T.

AU - White, Nicholas J.

AU - William, Timothy

AU - Woodrow, Charles J.

AU - Guerin, Philippe J.

AU - Price, Ric N.

PY - 2019/10/4

Y1 - 2019/10/4

N2 - Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.

AB - Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7–49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1–12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40–24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48–0.84), p = 0.0013 and 0.83 (0.73–0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99–1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01–0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10–0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01–0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.

UR - http://www.scopus.com/inward/record.url?scp=85072910601&partnerID=8YFLogxK

U2 - 10.1371/journal.pmed.1002928

DO - 10.1371/journal.pmed.1002928

M3 - Article

VL - 16

SP - 1

EP - 21

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 10

M1 - e1002928

ER -