Soluble Markers of Immune Activation Differentially Normalize and Selectively Associate with Improvement in AST, ALT, Albumin, and Transient Elastography During IFN-Free HCV Therapy

Abstract

Background:During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evaluation of liver damage stage. While a portion of the TE score is attributable to liver fibrosis and relatively irreversible damage, another component of the TE score is attributable to liver inflammation or edema. Markers of inflammation during chronic HCV infection include soluble markers of immune activation, which are also associated with morbid outcome (including cardiovascular disease and liver-disease progression). Whether soluble markers of immune activation or changes in their level during HCV therapy relate to normalization of AST, ALT, Albumin, or TE score, is not clear.Methods:We evaluated soluble markers of immune activation (plasma sCD14, IL-6, sCD163, autotaxin [ATX], and Mac2BP) and TE score, and their relationship in 20 HCV-infected patients before, during, and after HCV-directed IFN-free direct-acting antiviral (DAA) therapy. We evaluated normalization of parameters and the relationship between each over a 6-month window.Results:Before therapy, serum AST levels positively correlated with plasma levels of sCD14, sCD163, and Mac2BP, while ALT levels positively correlated with Mac2BP. Serum albumin level negatively correlated with plasma IL-6 and ATX levels. IFN-free therapy uniformly resulted in sustained virological response at 12 and 24 weeks after therapy completion. After initiation of therapy AST and ALT normalized, while levels of ATX, Mac2BP, sCD163, and TE score partially normalized over 6 months. Additionally, change in AST level and APRI score correlated with change in sCD163, IL-6, and Mac2BP levels, and change in ALT correlated with change in IL-6 and Mac2BP levels. Improvement in TE score correlated with a decrease in the level of sCD14 at week 4, and almost statistically significant with decrease in sCD14 at weeks 20-24 after initiation of IFN-free HCV therapy.Conclusions:Soluble markers of immune activation normalize or partially normalize at different rates after initiation of curative HCV DAA therapy, and TE scores improve, with wide variability in the degree of absolute improvement in liver stiffness from patient to patient. Decline magnitude of sCD14 was associated with improvement in TE score, while magnitude of improvement in AST correlated with reduction in sCD163 levels. These data provide support for a model where monocyte/Kupffer cell activation may account for a portion of the liver inflammation and edema, which is at least partially reversible following initiation of HCV DAA therapy.

Improvement of liver disease and inflammation in patients with advanced HCV-related cirrhosis after antiviral therapy

“…In our study overall, HCV clearance after DAA therapy promoted a signi cant improvement in severity scores of liver cirrhosis and many plasma biomarkers linked to in ammation (bacterial translocation, in ammatory response, and endothelial dysfunction) and coagulopathy. Our data are in concordance with a large number of previous studies that found a signi cant decrease in liver disease scores of HIV/HCV-coinfected patients [6,7,32,[43][44][45] and HCV-monoinfected patients [6][7][8][9][10][11][12][13][14] after HCV eradiation with DAA therapy; and also in plasma biomarkers of HIV/HCV-coinfected patients [18,[30][31][32][33][34] and HCV-monoinfected patients [15][16][17][18][19][20]. However, there is an important lack of consistency in these previous publications regarding the plasma biomarkers and liver severity scores evaluated, time-points used to take data or samples after the end of HCV treatment, statistical analysis used, and liver brosis stages included.…”

“…Previously published studies do not usually have a control group of HCV-monoinfected patients, or if they do, they do not analyze the impact of HIV infection on the evolution of plasma biomarkers and liver disease scores after HCV eradication with all-oral DAAs [18,[30][31][32][33][34]. In our study, baseline values of outcome measures (plasma biomarkers and liver disease scores) and their subsequent evolution after DAA therapy were very similar in HIV/HCV-coinfected and HCV-monoinfected patients.…”

“…Laursen et al [20] reported that the levels of macrophage activation markers (sCD163 and soluble mannose receptor) correlated with LSM values during follow-up in HCV-monoinfected patients. Kostadinova et al [32] showed that an improvement in LSM values correlated with a decrease in sCD14 levels after IFN-free HCV therapy. Additionally, plasma levels of sCD163, IL-6, and Mac2-binding protein correlated with changes in AST level and APRI score.…”

“…Similarly, DAA treatments against HCV infection also achieve elevated SVR rates [26,27] and delay CHC progression in HIV/HCVcoinfected patients [28,29]. Several reports have also shown a signi cant decrease in plasma biomarkers related to in ammation and immune activation after SVR with all-oral DAAs in HIV/HCV-coinfected patients [18,[30][31][32][33][34]. However, DAA therapy alone does not completely block uncontrolled in ammation and liver injury, particularly with advanced liver disease [35].…”

The impact of achieving a sustained virological response with direct-acting antivirals on serum autotaxin levels in chronic hepatitis C patients

“…Several reports suggested that the achievement of SVR with DAA therapy improves hepatic fibrosis in CHC patients [23,25]; however, the changes of serum ATX levels have been investigated in scarce studies in this context [16,[26][27][28] and its ability to reflect the regression of hepatic fibrosis remains uncertain. Therefore, we aimed to investigate the impact of achieving SVR with DAA therapy on serum ATX levels and whether these levels can reflect the regression of hepatic fibrosis in CHC patients.…”