Liver Function Test Abnormalities in Experimental and Clinical Plasmodium vivax Infection

Abstract

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ³ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days posttreatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ³ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; P = 0.02) for every log 10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ³ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; P = 0.06), this risk disappeared when corrected for parasite clearance burden (PCB). Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (³ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.

Development and evaluation of a new P. falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

“…The adverse events reported for both studies are in keeping with previous IBSM studies [9][10][11]28,29]. The asymptomatic raised liver enzymes, with no associated signi cant rise in bilirubin, have been reported in previous IBSM studies [30,31], sporozoite VIS [32] and in naturally occurring malaria [30,33]. Similarly, the reduction in white cell counts, especially lymphopenia and neutropenia have previously been reported in IBSM VIS, sporozoite VIS and clinical malaria [12,16,[34][35][36].…”

Plasmodium infection prevents recurrence and metastasis of hepatocellular carcinoma possibly via inhibition of the epithelial‑mesenchymal transition

“…Plasmodium is a genus of single-cell protozoa that causes malaria, which may enter hepatocytes for dormancy or reproduction and lead to cell rupture, release merozoites and invade red blood cells (17). Although Plasmodium stays in the liver and causes black colouring of the tissue due to the deposition of the Plasmodium pigment, it does not damage liver function (18). Our previous studies have demonstrated that Plasmodium infection inhibits tumour development and metastasis in a murine Lewis lung cancer model (19)(20)(21)(22)(23)(24).…”

Mapping T cell activation and differentiation at single cell resolution in naive hosts infected withPlasmodium vivax

“…Of note, there were no significant deviations in albumin or bilirubin in our volunteer cohort (Minassian et al, in preparation) indicating that the biosynthetic and metabolic functions of the liver have not been compromised. Elevations in ALT are therefore a marker of asymptomatic collateral tissue damage in CHMI, as previously suggested (33). Another limitation of this study is that infections had to be terminated at a parasite density much lower than would be observed in endemic settings.…”

“…Drug treatment is also unlikely to explain the increase in ALT observed in most volunteers. Liver injury is a common feature of clinical and experimental malaria and occurs independently of the drug used or the treatment regime (32)(33)(34). Furthermore, abnormal ALT levels significantly decrease 7-days after drug treatment in patients with severe malaria (80), suggesting that infection or inflammation is the driver of hepatocellular death.…”