Letter to the editor RE: Reuling et al., 2018 ‘liver injury in uncomplicated malaria is an overlooked phenomenon: An observational study’

Reuling et al. report that liver enzyme abnormalities (transient increases in aspartate transaminase (AST) and alanine transaminase (ALT)) [[1]Reuling I.J. de Jong G.M. Yap X.Z. Asghar M. Walk J. van de Schans L.A. et al.Liver injury in uncomplicated malaria is an overlooked phenomenon: an observational study.EBioMedicine. 2018; Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar] are common in experimental P. falciparum Controlled Human Malaria Infections (CHMI) in healthy volunteers and uncomplicated falciparum malaria in returning travellers. This prompted us to review prospectively collected data on these biochemical markers of liver injury from a recently published antimalarial treatment trial in patients with uncomplicated falciparum malaria in Southeast Asia [[2]van der Pluijm R.W. Tripura R. Hoglund R.M. Pyae Phyo A. Lek D. Ul Islam A. et al.Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.Lancet. 2020; 395: 1345-1360Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. We confined our analysis to patients treated with conventional artemisinin combination therapies (ACTs) (Table 1).Table 1Characteristics of patients included in the analysis; all values are median (IQR) or total number (%). DHA-PPQ: dihydroartemisinin-piperaquine; AS-MQ: artesunate-mefloquine; AL: artemether-lumefantrine; AST: Aspartate transaminase; ALT: alanine transaminase; ULN: Upper limit of normal. *Two patients suffered from a grade 3 (severe) ALT and/or AST increase which scored as a grade 3 level at day 7 (2).Day 0Day 3Day 7Day 28Peak concentration during studyNumber of subjects250250243229250Age27·0 (19·0-35·0)Gender (Male/total) (%)215/250 (86·0)215/250 (86·0)208/243 (85·6)197/229 (86·0)Temperature37·5 (36·9–38·1)36·4 (36·0–36·7)36·4 (36·0–36·7)36·3 (36·0–36·7)TreatmentDHA-PPQ (n, % of total)61 (24·4)61 (24·4)59 (24·3)50 (21·8)AS-MQ (n, % of total)73 (29·2)73 (29·2)71 (29·2)69 (30·1)AL (n, % of total)116 (46·4)116 (46·4)113 (46·5)110 (48·0)Parasitaemia at baseline (parasites/microliter)26,376 (8,672-70,462)AST (U/L)34 (28–42)30 (24–40)35 (29–47)31 (26–39)44 (34–59)ALT (U/L)24 (18–34)26 (19–36)34 (24–48)22 (17–31)38 (26–55)Alkaline phosphatase (U/L)255 (215–361)253 (204–340)257 (214–336)249 (206–334)289 (236–404)Bilirubine (total) umol/L1·0 (0·7–1·5)0·5 (0·3–0·6)0·5 (0·4–0·6)0·5 (0·4–0·7)1 (0·7–1·5)Liver enzyme abnormalitiesNone (< 1·0xULN)96 (38·4)117 (46·8)82 (33·7)113 (49·3)Mild (> 1·0 ≤ 2·5 × ULN)137 (54·8)120 (48·0)139 (57·2)109 (47·6)Moderate (> 2·5 ≤ 5·0xULN)16 (6·4)10 (4·0)18 (7·4)6 (2·6)Severe (> 5·0xULN)1 (0·4)3 (1·2)*4 (1·7)*1 (0·4) Open table in a new tab Of 250 patients enrolled, 7/250 (2·8%), had at least one significant increase (> 5·0x ULN) in AST and/or ALT (Fuji DRI-CHEM 4000I) during the study. Most of these increases were observed first at day 3. This compared to 16/187 (8·8%) in experimentally infected individuals in the CHMI model (p = 0.008). In our study, median (range; IQR) peak plasma AST was 44 U/L (21-505; 34–59) and ALT 38 U/L (9-404; 26–55), compared to 52 U/L (22-723; 43–85) and 69 U/L (13–870; 46–98) in the CHMI model despite 100 to 1000 times lower parasite densities. In a recent large randomised trial, comparing 4 different ACTs which recruited 4710 children with uncomplicated falciparum malaria, the incidence of a > 5-fold increases in ALT or AST after antimalarial treatment was below 2·0% [[3]West African Network for Clinical Trials of Antimalarial DPyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial.Lancet. 2018; 391: 1378-1390Summary Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. These incidence rates are well below the reported increases in transaminases in returning travellers. The high peak levels of ALT and AST and high incidence of severe transaminase abnormalities in the CHMI model at very low parasite densities deserve further attention, since the laboratory-adapted strains used in this model could have an altered pathogenicity. Other elements of the model might also contribute to the observed 'transaminitis'. Awareness of potential model related adverse events is important. 'False flags' could discredit novel antimalarials that would not be hepatotoxic in the treatment of uncomplicated malaria in the field. In an era of increasing antimalarial drug resistance problems, any unnecessary delay in the development of novel antimalarial drugs should be avoided. The authors declare no competing interests. Download .docx (.04 MB) Help with docx files Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyThis study shows that reversible liver injury is a common feature of uncomplicated falciparum malaria, most likely caused by an enduring pro-inflammatory response post treatment. The recognition of this phenomenon is of clinical relevance for individual patient care as well as clinical development of (new) antimalarial drugs. Full-Text PDF Open AccessIn response to the letter to the editor by Dondorp et al. RE: Reuling et al., 2018 'liver injury in uncomplicated malaria is an overlooked phenomenon: An observational study'Dondorp et al. highlight that the incidence of liver function test (LFT) abnormalities (> 5·0x the upper limit of normal (ULN)) in SE-Asian malaria patients after artemisinin combination therapies (ACTs) is roughly three times lower than observed in Controlled Human Malaria Infection (CHMI) studies in malaria naïve-Dutch volunteers and uncomplicated falciparum malaria in returning travelers [1,2]. This remarkable difference indeed requires further consideration. Full-Text PDF Open Access