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Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis

Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis
Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis
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 (PC 1/2 ) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC 1/2 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 PC 1/2 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 PC 1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC 1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC 1/2 by 8.1 % (95 % CI 3.2–12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC 1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC 1/2 (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 PC 1/2 since 2007. Conclusions Several factors affect PC 1/2 . As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC 1/2 data. Studies with frequent parasite count measurements to characterize PC 1/2 should be encouraged. In western Cambodia, where PC 1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.
1475-2875
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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., Faiz, M. Abul, Falade, Catherine, Flegg, Jennifer A., Fogg, Carole Lesley, Gonzalez, Raquel, Greenwood, Brian, Guérin, Philippe J., Guthmann, Jean-Paul, Hamed, Kamal, Hien, Tran Tinh, 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. and Winstanley, Peter A. (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 (359), 1-12. (doi:10.1186/s12936-015-0874-1).

Record type: Article

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 (PC 1/2 ) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC 1/2 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 PC 1/2 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 PC 1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC 1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC 1/2 by 8.1 % (95 % CI 3.2–12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC 1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC 1/2 (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 PC 1/2 since 2007. Conclusions Several factors affect PC 1/2 . As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC 1/2 data. Studies with frequent parasite count measurements to characterize PC 1/2 should be encouraged. In western Cambodia, where PC 1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

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Accepted/In Press date: 26 August 2015
Published date: 22 September 2015

Identifiers

Local EPrints ID: 437085
URI: http://eprints.soton.ac.uk/id/eprint/437085
ISSN: 1475-2875
PURE UUID: 44bc71aa-030d-436f-969b-934c55bff4af
ORCID for Carole Lesley Fogg: ORCID iD orcid.org/0000-0002-3000-6185

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Date deposited: 16 Jan 2020 17:34
Last modified: 17 Mar 2024 03:56

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Contributors

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

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