Artemether-lumefantrine and liver enzyme abnormalities in non-severe Plasmodium falciparum malaria in returned travellers: a retrospective comparative study with quinine-doxycycline in a Portuguese centre

Abstract

Background Artemisinin-based therapy is the current standard treatment for non-severe malaria due to Plasmodium falciparum. The potential for asymptomatic liver toxicity of this therapy and its implication in clinical practice is currently unknown. The aim of this study is to assess the hepatic function in patients treated with a standard three-day artemisinin-based regimen and to compare it with the quinine-doxycycline regimen.MethodsRetrospective and comparative study of returned adult travellers admitted with non-severe P. falciparum malaria. Fifty-seven patients were included: 19 treated with artemisinin-based therapy and 38 with quinine-doxycycline therapy.ResultsDuring treatment, when compared with quinine-doxycycline group, the artemisinin-lumefantrine group presented a higher proportion of significant liver enzyme abnormalities (42 vs. 5%, p < 0.01) and a higher peak value of aspartate aminotransferase (131 vs. 64 U/L, p < 0.01) and alanine aminotransferase (99 vs. 75 U/L, p = 0.05). None of the patients was symptomatic, there were no treatment interruptions and all patients achieved clinical cure.ConclusionsTreatment of uncomplicated falciparum malaria with artemisinin-based therapy might cause asymptomatic liver enzyme abnormalities in the first days of treatment. Nevertheless, these liver enzyme abnormalities seem to be harmless, asymptomatic and self-limited.

Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational Study

“…This study specifically advocates the relevance in relation to potential clinical implications in uncomplicated disease, which constitutes the vast majority of clinical malaria cases. This study highlights that LFT abnormalities can be severe (up to >20 xULN), but are apparently fully reversible upon parasitological cure, corroborating previous reports [ [25] , [26] , [27] ].…”

“…Our findings reflect a need to understand and reassess LFT abnormalities in malaria. This will have significant impact on clinical decision-making and in drug development, where they are often interpreted as drug-induced liver injury, particularly in malaria drug studies [ 27 , 42 ]. For example, drug-related serious adverse events in a recent multicentre trial comparing pyronaridine–artesunate or dihydroartemisinin–piperaquine versus current first-line therapies for uncomplicated malaria were associated mainly with increased liver enzymes [ 43 ].…”

The Dynamics of Liver Function Test Abnormalities after Malaria Infection: A Retrospective Observational Study

“…This is in contrast to other studies associating artemisinin-containing treatment regimens, and presumably more rapid parasite clearance, with LFT elevations. 28 Plasmodium falciparum infection was associated with a higher frequency of abnormal LFTs overall. However, when the three time period groups were compared, the proportion of P. falciparum cases compared with P. vivax cases was only different between the normal and early transaminase elevation groups.…”

“…Peaks in transaminase levels after treatment have also been recently reported; these could represent a distinct type of malaria-associated liver injury. 28 – 31 In a small retrospective comparative European study, asymptomatic transaminase elevation was observed in returned travelers hospitalized for malaria after treatment with the artemisinin-based combination therapy artemether–lumefantrine. The authors postulated that the rapid parasiticidal effect of the antimalarial treatment may promote accelerated hepatic heme loading and oxidative stress.…”

“…The authors postulated that the rapid parasiticidal effect of the antimalarial treatment may promote accelerated hepatic heme loading and oxidative stress. 28 Liver injury through this proposed mechanism is not exactly an adverse drug reaction but rather may be influenced by factors, such as parasite burden, rate of clearance, and host heme metabolism. In prospective trials using the induced blood stage malaria (IBSM) model in healthy malaria-naive participants, asymptomatic moderate (2.5–5.0 × ULN) to more rarely severe (> 5.1 × ULN) elevations of transaminase enzymes have been reported in a subset of participants.…”