Association of IL28B genotype with fibrosis progression and clinical outcomes in patients with chronic hepatitis C: a longitudinal analysis

Abstract

Interleukin (IL)28B polymorphisms are associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to therapy. Whether IL28B genotype affects fibrosis progression or clinical outcome is unclear. Our aim was to study the relationship between IL28B genotype and both histological and clinical outcomes in patients with chronic hepatitis C (CHC). Hepatic fibrosis was scored using the Ishak (0-6) scale; progression was defined as a 2-point increase in Ishak score between biopsies. Multiple logistic and Cox regressions were used to identify variables associated with fibrosis progression. In all, 1,483 patients were included in a baseline cross-sectional analysis, from which 276 were eligible for a paired biopsy analysis (median time between biopsies 4 years), and 400 for a clinical outcome analysis. At baseline biopsy, patients with IL28B CC genotype had significantly higher portal inflammation (2.4 versus 2.2) and alanine aminotransferase (ALT) levels (133 versus 105 U/L; P < 0.05 for all). In the paired biopsy analysis, there was no difference in the frequency of fibrosis progression between patients with IL28B CC and non-CC genotypes (17% versus 23%). In logistic regression, only higher baseline alkaline phosphatase, lower platelets, and greater hepatic steatosis were associated with fibrosis progression. Patients with IL28B CC were twice as likely to develop adverse clinical outcomes compared to non-CC (32% versus 16%; P = 0.007).

Conclusion: IL28B CC genotype was associated with greater hepatic necroinflammation, higher ALT, and worse clinical outcomes in CHC patients. This suggests that IL28B CC is associated with a state of enhanced immunity that, on the one hand, can promote viral clearance, but alternately can increase necroinflammation and hepatic decompensation without enhancing fibrosis progression.

Figure 1

Derivation of the 3 analyses Cohorts: for the baseline analysis: There were 1382 subjects enrolled in the HALT-C trial and 309 followed at NIH. 145 subjects from the HALT-C cohort were excluded either for missing IL28B results n=143 or missing histology data n=2 and 63 subjects from the NIH cohort were excluded either for missing IL28B results n=58 or missing histology data n=5, leaving 1483 for analysis.*Clinical outcome cohort: Only subjects randomized to the control arm of the HALT-C trial because data on the clinical outcomes were prospectively collected over 3.85 years. This was not done for the NIH cohort. **Paired biopsy cohort: For this analysis we included only patients with paired liver biopsies a minimum of 1 year apart (and no more than 10 years apart) and absence of cirrhosis on the baseline biopsy.

Figure 2

Frequency of IL28B genotypes by HCV viral genotype (Cross-sectional analysis): 1483 patients were included in the cross-sectional analysis.

Figure 3

Life table analysis of clinical outcomes by IL28B genotypes: Clinical outcomes were defined as death, ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, hepatocellular carcinoma and increase in Child-Turcotte-Pugh score by ≥2 points at 2 consecutive study visits) in 400 untreated HALT-C subjects prospectively observed for 3.8 years.