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The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data

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Title: The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data
Authors: Okell, L
Bretscher, MT
Dahal, P
Griffin, J
Stepniewska, K
Bassat, Q
Baudin, E
D'Alessandro, U
Djimde, A
Dorsey, G
Espie, E
Fofana, B
Gonzalez, R
Juma, E
Karema, C
Lasry, E
Lell, B
Lima, N
Menendez, C
Mombo-Ngoma, G
Moreira, C
Nikiema, F
Ouedraogo, J
Staedke, S
Tinto, H
Valea, I
Yeka, A
Ghani, A
Guerin, P
Item Type: Journal Article
Abstract: Background: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programmes combined with sulfadoxine-pyrimethamine. Whilst artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. Methods: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n=4214 individuals). The time to PCR-confirmed re-infection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to re-infection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. Results: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to re-infection in multivariate models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~2-fold longer protection than AL. Conversely at a higher prevalence of 86Y and 76T mutant parasites (>80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-five year old children when the drugs were used as first-line treatments in areas with high, seasonal transmission. Conclusion: Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.
Issue Date: 25-Feb-2020
Date of Acceptance: 9-Jan-2020
URI: http://hdl.handle.net/10044/1/76878
DOI: 10.1186/s12916-020-1494-3
ISSN: 1741-7015
Publisher: BioMed Central
Start Page: 1
End Page: 17
Journal / Book Title: BMC Medicine
Volume: 18
Issue: 47
Copyright Statement: © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Medical Research Council (MRC)
Medicines for Malaria Venture
The Royal Society
Medical Research Council (MRC)
Bill & Melinda Gates Foundation
Funder's Grant Number: MR/K010174/1B
PO14/00561
DH140134
MR/R015600/1
OPP1068440
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Malaria
Artemisinin
Drug
Lumefantrine
Amodiaquine
Trial
Mathematical model
mdr1
Crt
PLASMODIUM-FALCIPARUM MALARIA
ANTIMALARIAL-DRUG RESISTANCE
SULFADOXINE-PYRIMETHAMINE
MOLECULAR MARKERS
DIHYDROARTEMISININ-PIPERAQUINE
GENETIC-STRUCTURE
PREGNANT-WOMEN
SELECTION
POLYMORPHISMS
CHEMOPREVENTION
Amodiaquine
Artemisinin
Crt
Drug
Lumefantrine
Malaria
Mathematical model
Trial
mdr1
11 Medical and Health Sciences
General & Internal Medicine
Publication Status: Published
Online Publication Date: 2020-02-25
Appears in Collections:Faculty of Medicine
School of Public Health