Serum fibrosis marker levels decrease after successful antiviral treatment in chronic hepatitis C patients with advanced fibrosis

Abstract

Background & aims: Serum fibrosis marker levels during the lead-in treatment phase of patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial were determined.

Methods: Week 0, 24, 48, and 72 serum samples were analyzed for YKL-40, tissue inhibitor of matrix metalloproteinase-1, amino-terminal peptide of type III procollagen (PIIINP), and hyaluronic acid (HA) levels. All 456 chronic hepatitis C (CHC) patients received peginterferon alfa 2a and ribavirin for 24 to 48 weeks.

Results: Mean age was 49.2 years, 71% were male, and 39% had cirrhosis. Lower pretreatment serum YKL-40, tissue inhibitor of matrix metalloproteinase-1, PIIINP, and HA levels were associated significantly with week-20 virologic response (P < .0001). In multivariate analysis, non-1 CHC genotype, non-black race, prior interferon monotherapy, and lower baseline serum aspartate aminotransferase/alanine aminotransferase levels and log(10)YKL-40 levels were associated independently with week-20 virologic response. Statistically significant declines in all marker levels were observed at week 72 compared with baseline in the 81 patients with a sustained virologic response, but not in the 72 patients with breakthrough or relapse. At weeks 24 and 48, significant increases were observed in serum PIIINP and HA levels compared with baseline in virologic responders and nonresponders (P < .0001).

Conclusions: Pretreatment YKL-40 levels are an independent predictor of initial virologic response to peginterferon and ribavirin treatment. Levels of all 4 serum fibrosis markers decreased significantly in the SVR patients, consistent with reduced hepatic fibrogenesis. Measuring serum fibrosis marker levels before and after antiviral therapy may provide important prognostic information in CHC patients.

Figure 1

Serum fibrosis marker levels at weeks 0 and 24. A). The log₁₀ YKL-40 levels were significantly lower at week 24 in the partial (p=0.0008) and non-responders (p=0.0005) compared to week 0 but were unchanged in the complete responders. In contrast, the week 24 log₁₀ hyaluronic acid levels were all significantly increased compared to week 0 in all 3 patient groups (p < 0.0001). B). The serum PIIINP levels were significantly higher at week 24 compared to week 0 in all 3 patient groups; complete responders (p < 0.0001), partial responders (p=0.012), non-responders (p=0.005). C) The serum TIMP-1 levels only significantly declined at week 24 compared to week 0 in the complete responders (p=0.048). NOTE: Only P-values for significant differences, comparing Week 0 to 24, are shown for each marker.

Figure 2

Serum fibrosis marker levels before, during and after 48 weeks of pegylated interferon and ribavirin treatment. (□ = Sustained virological responders; ▲ = Breakthru/relapsers). A). Log₁₀ YKL-40 levels were significantly lower at week 72 compared to baseline in the SVR patients (p=0.0002) and remained unchanged in the breakthrough/relapsers B). Log₁₀ hyaluronic acid levels were significantly lower at week 72 in the SVR patients (p < 0.0001) as well as the breakthrough/relapsers compared to week 0 (p= 0.007). C). Serum PIIINP levels significantly declined at week 72 compared to week 0 in the SVR patients (p = 0.0004) but were unchanged in the breakthrough/relapsers (p= 0.21) D). Serum TIMP-1 levels only significantly declined at week 72 compared to baseline in the SVR patients (p=0.0022).

Figure 3

Multivariate models of week 20 virological response in 456 HALT-C Trial patients. Model 1 which was derived from the overall HALT-C cohort consists of non-1 HCV genotype, HCV RNA level, non-black race, prior interferon monotherapy, and cirrhosis had a c-statistic of 0.68 (95% CI: 0.63, 0.73). The addition of baseline log₁₀ YKL-40 levels to Model 1 had a c-statistic of 0.76 (95% CI: 0.72, 0.81) and was significantly better than model 1 alone in predicting week 20 virological response (p= 0.0004). In comparison, Model 2 which was derived from the current dataset and includes baseline log₁₀ YKL-40, serum AST/ALT, non-black race, interferon monotherapy, and non-1 HCV genotype had a c-statistic of 0.80 (95% CI: 0.76, 0.84) and was significantly better at predicting week 20 virological response compared to Model 1 (p < 0.0001) and Model 1 with log₁₀ YKL-40 (p=0.0080)