Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C

Abstract

Objectives: The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC).

Methods: 462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ≥2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child-Turcotte-Pugh) score to ≥7.

Results: Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663).

Conclusion: Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Trial registration: ClinicalTrials.gov NCT00006164.

Figure 1

Risk of developing a primary clinical outcome during follow-up. The 324 HALT-C Trial patients with a risk score of under − 2.5 have a low risk of a clinical outcome (8%) while the 44 patients with a risk score > − 1.7 are at the highest risk of a clinical outcome (65%) and would warrant the most intensive monitoring.

Figure 2

Serum fibrosis marker levels in HALT-C patients with and without clinical progression. 2A). Serum YKL-40 levels significantly changed over time in the 69 patients with disease progression and in the 393 without disease progression (p= 0.0026). YKL-40 levels also differed significantly in the progressors compared to the non-progressors (p=< 0.0001), but the changes over time did not differ by outcome group (p= 0.21). 2B). Serum TIMP-1 levels also changed significantly over time (p< 0.0001), were significantly different in progressors compared to non-progressors (p < 0.0001), and the changes over time did differ by outcome group (p=0.0023). 2C). Serum PIIINP levels changed significantly over time (p < 0.001), were significantly different in the two outcome groups (p < 0.0001), and the changes over time did differ by outcome group (p < 0.0001). 2D). Serum HA levels significantly changed over time (p< 0.0001), were significantly different in the two outcome groups (p< 0.0001) and also differed over time by outcome group (p = 0.0111).

Figure 2

Serum fibrosis marker levels in HALT-C patients with and without clinical progression. 2A). Serum YKL-40 levels significantly changed over time in the 69 patients with disease progression and in the 393 without disease progression (p= 0.0026). YKL-40 levels also differed significantly in the progressors compared to the non-progressors (p=< 0.0001), but the changes over time did not differ by outcome group (p= 0.21). 2B). Serum TIMP-1 levels also changed significantly over time (p< 0.0001), were significantly different in progressors compared to non-progressors (p < 0.0001), and the changes over time did differ by outcome group (p=0.0023). 2C). Serum PIIINP levels changed significantly over time (p < 0.001), were significantly different in the two outcome groups (p < 0.0001), and the changes over time did differ by outcome group (p < 0.0001). 2D). Serum HA levels significantly changed over time (p< 0.0001), were significantly different in the two outcome groups (p< 0.0001) and also differed over time by outcome group (p = 0.0111).

Figure 2

Serum fibrosis marker levels in HALT-C patients with and without clinical progression. 2A). Serum YKL-40 levels significantly changed over time in the 69 patients with disease progression and in the 393 without disease progression (p= 0.0026). YKL-40 levels also differed significantly in the progressors compared to the non-progressors (p=< 0.0001), but the changes over time did not differ by outcome group (p= 0.21). 2B). Serum TIMP-1 levels also changed significantly over time (p< 0.0001), were significantly different in progressors compared to non-progressors (p < 0.0001), and the changes over time did differ by outcome group (p=0.0023). 2C). Serum PIIINP levels changed significantly over time (p < 0.001), were significantly different in the two outcome groups (p < 0.0001), and the changes over time did differ by outcome group (p < 0.0001). 2D). Serum HA levels significantly changed over time (p< 0.0001), were significantly different in the two outcome groups (p< 0.0001) and also differed over time by outcome group (p = 0.0111).

Figure 2

Serum fibrosis marker levels in HALT-C patients with and without clinical progression. 2A). Serum YKL-40 levels significantly changed over time in the 69 patients with disease progression and in the 393 without disease progression (p= 0.0026). YKL-40 levels also differed significantly in the progressors compared to the non-progressors (p=< 0.0001), but the changes over time did not differ by outcome group (p= 0.21). 2B). Serum TIMP-1 levels also changed significantly over time (p< 0.0001), were significantly different in progressors compared to non-progressors (p < 0.0001), and the changes over time did differ by outcome group (p=0.0023). 2C). Serum PIIINP levels changed significantly over time (p < 0.001), were significantly different in the two outcome groups (p < 0.0001), and the changes over time did differ by outcome group (p < 0.0001). 2D). Serum HA levels significantly changed over time (p< 0.0001), were significantly different in the two outcome groups (p< 0.0001) and also differed over time by outcome group (p = 0.0111).

Figure 3

Serum fibrosis marker levels over time by treatment group. 3A) Serum YKL-40 levels changed significantly over time in both groups of patients (p< 0.0001) but the changes did not differ by treatment group (p=0.23). 3B). Serum TIMP-1 levels changed significantly over time (p< 0.0001), but the changes did not differ by treatment group (p= 0.34). 3C). Serum PIIINP levels increased significantly over time in the two treatment groups (p< 0.0001). The levels were higher in the peginterferon-treated patients (p= 0.0015) and the changes over time were greater in the peginterferon treated patients (p< 0.0001). 3D). Serum HA levels also changed significantly over time in the two patient groups P< 0.0001), were higher in the peginterferon treated patients (p= 0.0007), and the changes over time were greatest in the peginterferon group (p< 0.0001).

Figure 3

Serum fibrosis marker levels over time by treatment group. 3A) Serum YKL-40 levels changed significantly over time in both groups of patients (p< 0.0001) but the changes did not differ by treatment group (p=0.23). 3B). Serum TIMP-1 levels changed significantly over time (p< 0.0001), but the changes did not differ by treatment group (p= 0.34). 3C). Serum PIIINP levels increased significantly over time in the two treatment groups (p< 0.0001). The levels were higher in the peginterferon-treated patients (p= 0.0015) and the changes over time were greater in the peginterferon treated patients (p< 0.0001). 3D). Serum HA levels also changed significantly over time in the two patient groups P< 0.0001), were higher in the peginterferon treated patients (p= 0.0007), and the changes over time were greatest in the peginterferon group (p< 0.0001).

Figure 3

Serum fibrosis marker levels over time by treatment group. 3A) Serum YKL-40 levels changed significantly over time in both groups of patients (p< 0.0001) but the changes did not differ by treatment group (p=0.23). 3B). Serum TIMP-1 levels changed significantly over time (p< 0.0001), but the changes did not differ by treatment group (p= 0.34). 3C). Serum PIIINP levels increased significantly over time in the two treatment groups (p< 0.0001). The levels were higher in the peginterferon-treated patients (p= 0.0015) and the changes over time were greater in the peginterferon treated patients (p< 0.0001). 3D). Serum HA levels also changed significantly over time in the two patient groups P< 0.0001), were higher in the peginterferon treated patients (p= 0.0007), and the changes over time were greatest in the peginterferon group (p< 0.0001).

Figure 3

Serum fibrosis marker levels over time by treatment group. 3A) Serum YKL-40 levels changed significantly over time in both groups of patients (p< 0.0001) but the changes did not differ by treatment group (p=0.23). 3B). Serum TIMP-1 levels changed significantly over time (p< 0.0001), but the changes did not differ by treatment group (p= 0.34). 3C). Serum PIIINP levels increased significantly over time in the two treatment groups (p< 0.0001). The levels were higher in the peginterferon-treated patients (p= 0.0015) and the changes over time were greater in the peginterferon treated patients (p< 0.0001). 3D). Serum HA levels also changed significantly over time in the two patient groups P< 0.0001), were higher in the peginterferon treated patients (p= 0.0007), and the changes over time were greatest in the peginterferon group (p< 0.0001).