Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative

An individual patient data meta-analysis

Salim Abdulla, Elizabeth A. Ashley, Quique Bassat, Delia Bethell, Anders Björkman, Steffen Borrmann, Umberto D’Alessandro, Prabin Dahal, Nicholas P. Day, Mahamadou Diakite, Abdoulaye A. Djimde, Arjen M. Dondorp, Socheat Duong, Michael D. Edstein, Rick M. Fairhurst, M. Abul Faiz, Catherine Falade, Jennifer A. Flegg, Carole Fogg, Raquel Gonzalez & 31 others Brian Greenwood, Philippe J. Guérin, Jean Paul Guthmann, Kamal Hamed, Tran Tinh Hien, Ye Htut, Elizabeth Juma, Pharath Lim, Andreas Mårtensson, Mayfong Mayxay, Olugbenga A. Mokuolu, Clarissa Moreira, Paul Newton, Harald Noedl, Francois Nosten, Bernhards R. Ogutu, Marie A. Onyamboko, Seth Owusu-Agyei, Aung Pyae Phyo, Zul Premji, Ric N. Price, Sasithon Pukrittayakamee, Michael Ramharter, Issaka Sagara, Youry Se, Seila Suon, Kasia Stepniewska, Stephen A. Ward, Nicholas J. White, Peter A. Winstanley, WWARN Parasite Clearance Study Group

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    Abstract

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up.

    Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive.

    Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007.

    Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

    Original languageEnglish
    Article number359
    Pages (from-to)1-12
    Number of pages12
    JournalMalaria Journal
    Volume14
    Issue number1
    DOIs
    Publication statusPublished - 2015

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    Falciparum Malaria
    Meta-Analysis
    Parasites
    Cambodia
    Recurrence
    artemisinine
    Myanmar
    Parasitemia
    Vietnam
    Vulnerable Populations
    Thailand
    Plasmodium falciparum
    Biomass
    Half-Life

    Cite this

    Abdulla, S., Ashley, E. A., Bassat, Q., Bethell, D., Björkman, A., Borrmann, S., ... WWARN Parasite Clearance Study Group (2015). Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: An individual patient data meta-analysis. Malaria Journal, 14(1), 1-12. [359]. https://doi.org/10.1186/s12936-015-0874-1
    Abdulla, Salim ; Ashley, Elizabeth A. ; Bassat, Quique ; Bethell, Delia ; Björkman, Anders ; Borrmann, Steffen ; D’Alessandro, Umberto ; Dahal, Prabin ; Day, Nicholas P. ; Diakite, Mahamadou ; Djimde, Abdoulaye A. ; Dondorp, Arjen M. ; Duong, Socheat ; Edstein, Michael D. ; Fairhurst, Rick M. ; Abul Faiz, M. ; Falade, Catherine ; Flegg, Jennifer A. ; Fogg, Carole ; Gonzalez, Raquel ; Greenwood, Brian ; Guérin, Philippe J. ; Guthmann, Jean Paul ; Hamed, Kamal ; Tinh Hien, Tran ; Htut, Ye ; Juma, Elizabeth ; Lim, Pharath ; Mårtensson, Andreas ; Mayxay, Mayfong ; Mokuolu, Olugbenga A. ; Moreira, Clarissa ; Newton, Paul ; Noedl, Harald ; Nosten, Francois ; Ogutu, Bernhards R. ; Onyamboko, Marie A. ; Owusu-Agyei, Seth ; Pyae Phyo, Aung ; Premji, Zul ; Price, Ric N. ; Pukrittayakamee, Sasithon ; Ramharter, Michael ; Sagara, Issaka ; Se, Youry ; Suon, Seila ; Stepniewska, Kasia ; Ward, Stephen A. ; White, Nicholas J. ; Winstanley, Peter A. ; WWARN Parasite Clearance Study Group. / Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : An individual patient data meta-analysis. In: Malaria Journal. 2015 ; Vol. 14, No. 1. pp. 1-12.
    @article{515db35c4fa549aab6f2d30535082f06,
    title = "Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: An individual patient data meta-analysis",
    abstract = "Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 {\%}) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 {\%}. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 {\%} (95 {\%} CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 {\%} CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 {\%} CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.",
    keywords = "Artemisinin resistance, Drug resistance, Malaria, Parasite clearance, Plasmodium falciparum",
    author = "Salim Abdulla and Ashley, {Elizabeth A.} and Quique Bassat and Delia Bethell and Anders Bj{\"o}rkman and Steffen Borrmann and Umberto D’Alessandro and Prabin Dahal and Day, {Nicholas P.} and Mahamadou Diakite and Djimde, {Abdoulaye A.} and Dondorp, {Arjen M.} and Socheat Duong and Edstein, {Michael D.} and Fairhurst, {Rick M.} and {Abul Faiz}, M. and Catherine Falade and Flegg, {Jennifer A.} and Carole Fogg and Raquel Gonzalez and Brian Greenwood and Gu{\'e}rin, {Philippe J.} and Guthmann, {Jean Paul} and Kamal Hamed and {Tinh Hien}, Tran and Ye Htut and Elizabeth Juma and Pharath Lim and Andreas M{\aa}rtensson and Mayfong Mayxay and Mokuolu, {Olugbenga A.} and Clarissa Moreira and Paul Newton and Harald Noedl and Francois Nosten and Ogutu, {Bernhards R.} and Onyamboko, {Marie A.} and Seth Owusu-Agyei and {Pyae Phyo}, Aung and Zul Premji and Price, {Ric N.} and Sasithon Pukrittayakamee and Michael Ramharter and Issaka Sagara and Youry Se and Seila Suon and Kasia Stepniewska and Ward, {Stephen A.} and White, {Nicholas J.} and Winstanley, {Peter A.} and {WWARN Parasite Clearance Study Group}",
    year = "2015",
    doi = "10.1186/s12936-015-0874-1",
    language = "English",
    volume = "14",
    pages = "1--12",
    journal = "Malaria Journal",
    issn = "1475-2875",
    publisher = "BioMed Central",
    number = "1",

    }

    Abdulla, S, Ashley, EA, Bassat, Q, Bethell, D, Björkman, A, Borrmann, S, D’Alessandro, U, Dahal, P, Day, NP, Diakite, M, Djimde, AA, Dondorp, AM, Duong, S, Edstein, MD, Fairhurst, RM, Abul Faiz, M, Falade, C, Flegg, JA, Fogg, C, Gonzalez, R, Greenwood, B, Guérin, PJ, Guthmann, JP, Hamed, K, Tinh Hien, T, Htut, Y, Juma, E, Lim, P, Mårtensson, A, Mayxay, M, Mokuolu, OA, Moreira, C, Newton, P, Noedl, H, Nosten, F, Ogutu, BR, Onyamboko, MA, Owusu-Agyei, S, Pyae Phyo, A, Premji, Z, Price, RN, Pukrittayakamee, S, Ramharter, M, Sagara, I, Se, Y, Suon, S, Stepniewska, K, Ward, SA, White, NJ, Winstanley, PA & WWARN Parasite Clearance Study Group 2015, 'Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: An individual patient data meta-analysis', Malaria Journal, vol. 14, no. 1, 359, pp. 1-12. https://doi.org/10.1186/s12936-015-0874-1

    Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : An individual patient data meta-analysis. / Abdulla, Salim; Ashley, Elizabeth A.; Bassat, Quique; Bethell, Delia; Björkman, Anders; Borrmann, Steffen; D’Alessandro, Umberto; Dahal, Prabin; Day, Nicholas P.; Diakite, Mahamadou; Djimde, Abdoulaye A.; Dondorp, Arjen M.; Duong, Socheat; Edstein, Michael D.; Fairhurst, Rick M.; Abul Faiz, M.; Falade, Catherine; Flegg, Jennifer A.; Fogg, Carole; Gonzalez, Raquel; Greenwood, Brian; Guérin, Philippe J.; Guthmann, Jean Paul; Hamed, Kamal; Tinh Hien, Tran; Htut, Ye; Juma, Elizabeth; Lim, Pharath; Mårtensson, Andreas; Mayxay, Mayfong; Mokuolu, Olugbenga A.; Moreira, Clarissa; Newton, Paul; Noedl, Harald; Nosten, Francois; Ogutu, Bernhards R.; Onyamboko, Marie A.; Owusu-Agyei, Seth; Pyae Phyo, Aung; Premji, Zul; Price, Ric N.; Pukrittayakamee, Sasithon; Ramharter, Michael; Sagara, Issaka; Se, Youry; Suon, Seila; Stepniewska, Kasia; Ward, Stephen A.; White, Nicholas J.; Winstanley, Peter A.; WWARN Parasite Clearance Study Group.

    In: Malaria Journal, Vol. 14, No. 1, 359, 2015, p. 1-12.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative

    T2 - An individual patient data meta-analysis

    AU - Abdulla, Salim

    AU - Ashley, Elizabeth A.

    AU - Bassat, Quique

    AU - Bethell, Delia

    AU - Björkman, Anders

    AU - Borrmann, Steffen

    AU - D’Alessandro, Umberto

    AU - Dahal, Prabin

    AU - Day, Nicholas P.

    AU - Diakite, Mahamadou

    AU - Djimde, Abdoulaye A.

    AU - Dondorp, Arjen M.

    AU - Duong, Socheat

    AU - Edstein, Michael D.

    AU - Fairhurst, Rick M.

    AU - Abul Faiz, M.

    AU - Falade, Catherine

    AU - Flegg, Jennifer A.

    AU - Fogg, Carole

    AU - Gonzalez, Raquel

    AU - Greenwood, Brian

    AU - Guérin, Philippe J.

    AU - Guthmann, Jean Paul

    AU - Hamed, Kamal

    AU - Tinh Hien, Tran

    AU - Htut, Ye

    AU - Juma, Elizabeth

    AU - Lim, Pharath

    AU - Mårtensson, Andreas

    AU - Mayxay, Mayfong

    AU - Mokuolu, Olugbenga A.

    AU - Moreira, Clarissa

    AU - Newton, Paul

    AU - Noedl, Harald

    AU - Nosten, Francois

    AU - Ogutu, Bernhards R.

    AU - Onyamboko, Marie A.

    AU - Owusu-Agyei, Seth

    AU - Pyae Phyo, Aung

    AU - Premji, Zul

    AU - Price, Ric N.

    AU - Pukrittayakamee, Sasithon

    AU - Ramharter, Michael

    AU - Sagara, Issaka

    AU - Se, Youry

    AU - Suon, Seila

    AU - Stepniewska, Kasia

    AU - Ward, Stephen A.

    AU - White, Nicholas J.

    AU - Winstanley, Peter A.

    AU - WWARN Parasite Clearance Study Group

    PY - 2015

    Y1 - 2015

    N2 - Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

    AB - Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

    KW - Artemisinin resistance

    KW - Drug resistance

    KW - Malaria

    KW - Parasite clearance

    KW - Plasmodium falciparum

    UR - http://www.scopus.com/inward/record.url?scp=84942511604&partnerID=8YFLogxK

    U2 - 10.1186/s12936-015-0874-1

    DO - 10.1186/s12936-015-0874-1

    M3 - Article

    VL - 14

    SP - 1

    EP - 12

    JO - Malaria Journal

    JF - Malaria Journal

    SN - 1475-2875

    IS - 1

    M1 - 359

    ER -