Asymptomatic recrudescence after artemether-lumefantrine treatment for uncomplicated falciparum malaria: a systematic review and meta-analysis

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.

Keywords: Artemether–lumefantrine; Artemisinin-based combination therapy; Clinical trials; Malaria; Plasmodium falciparum; Systematic review; Transmission; Treatment failure.

Fig. 1

Flowchart showing the origin of all studies included in this review

Fig. 2

Model predictions for the proportion of recrudescences that are symptomatic. The proportion of recrudescences that are symptomatic decreases with transmission intensity, and is higher in young children. Points show data and lines are predictions from the multivariable regression modelling with 95% credible intervals as shaded areas. Results were generated from the best-fit model (Table 2), which included covariates for transmission intensity (measured as malaria prevalence) and age (binary variable, indicating trials that only enrolled children under 72 months old)