Asymptomatic recrudescence after artemether-lumefantrine treatment for uncomplicated falciparum malaria: a systematic review and meta-analysis
File(s)
Published version
Author(s)
Mumtaz, Rida
Okell, Lucy C
Challenger, Joseph
Type
Journal Article
Abstract
Background
In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated.
Methods
A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study.
Results
Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic.
Conclusions
AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.
In clinical trials of therapy for uncomplicated Plasmodium falciparum, there are usually some patients who fail treatment even in the absence of drug resistance. Treatment failures, which can be due to recrudescence or re-infection, are categorized as ‘clinical’ or ‘parasitological’ failures, the former indicating that symptoms have returned. Asymptomatic recrudescence has public health implications for continued malaria transmission and may be important for the spread of drug-resistant malaria. As the number of recrudescences in an individual trial is often low, it is difficult to assess how commonplace asymptomatic recrudescence is, and with what factors it is associated.
Methods
A systematic literature review was carried out on clinical trials of artemether-lumefantrine (AL) in patients seeking treatment for symptomatic uncomplicated falciparum malaria, and information on symptoms during treatment failure was recorded. Only treatment failures examined by polymerase chain reaction (PCR) were included, so as to exclude re-infections. A multivariable Bayesian regression model was used to explore factors potentially explaining the proportion of recrudescent infections which are symptomatic across the trials included in the study.
Results
Across 60 published trials, including 9137 malaria patients, 37.8% [95% CIs (26.6–49.4%)] of recrudescences were symptomatic. A positive association was found between transmission intensity and the observed proportion of recrudescences that were asymptomatic. Symptoms were more likely to return in trials that only enrolled children aged < 72 months [odds ratio = 1.62, 95% CIs (1.01, 2.59)]. However, 84 studies had to be excluded from this analysis, as recrudescences were not specified as symptomatic or asymptomatic.
Conclusions
AL, the most widely used treatment for uncomplicated P. falciparum in Africa, remains a highly efficacious drug in most endemic countries. However in the small proportion of patients where AL does not clear parasitaemia, the majority of patients do not develop symptoms again and thus would be unlikely to seek another course of treatment. This continued asymptomatic parasite carriage in patients who have been treated may have implications for drug-resistant parasites being introduced into high-transmissions settings.
Date Issued
2020-12-09
Date Acceptance
2020-11-25
Citation
Malaria Journal, 2020, 19
ISSN
1475-2875
Publisher
BioMed Central
Journal / Book Title
Malaria Journal
Volume
19
Copyright Statement
© 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.
License URL
Sponsor
The Royal Society
Medicines for Malaria Venture
Medical Research Council (MRC)
Grant Number
DH140134
PO14/00561
MR/R015600/1
Subjects
Artemether–lumefantrine
Artemisinin-based combination therapy
Clinical trials
Malaria
Plasmodium falciparum
Systematic review
Transmission
Treatment failure
Tropical Medicine
0605 Microbiology
1108 Medical Microbiology
1117 Public Health and Health Services
Publication Status
Published
Article Number
453