[27] Fourth, it is possible that differences in baseline characteristics between the two cohorts may account for some of the associations found with IL28B. However, analyzing the cohorts separately ZIETDFMK yielded similar findings (Supporting Table S1). Finally, clinical outcomes are much better endpoints of disease progression than fibrosis staging, and therefore should be the more biologically relevant measure of phenotype-genotype correlation. IL28B

genotype CC was associated with a lower frequency of HCV genotype 1 infection and hepatic steatosis compared to IL28B genotypes CT or TT. These appear to be consistent findings among studies that have examined these relationships.[11, 28-30] The reason for the association with HCV genotype 1 is not clear but the findings suggest that either HCV non-1 genotypes preferentially

infect subjects with IL28B genotype CC or that HCV genotype 1 infections may be more effectively cleared by those with learn more IL28B CC genotype compared to non-1 HCV genotype. It is possible that prior therapy of the HALT-C cohort may have introduced bias into the analysis by enrichment of the HALT-C cohort (predominantly HCV genotype 1) with IL28B non-CC genotypes. However, when we examined the NIH cohort, all of whom were untreated, the same association with IL28B genotype and HCV genotype was found. This study has several strengths that are worth highlighting. Patients were derived from two pedigreed cohorts that encompassed a wide spectrum of disease severity. Liver biopsies were evaluated by a panel of expert hepatopathologists in the majority of cases and a robust definition of fibrosis progression was used,

a 2-point increase in 上海皓元 fibrosis score, that should limit the effect of sampling error on liver biopsy. No previous study has used paired biopsies, which we believe is the best approach to explore the relationship between IL28B and disease progression. Subjects in the HALT-C trial were prospectively followed every 3 months for the development of clinical decompensation and all events were adjudicated by a panel of three rotating investigators before being entered into the trial database. A potential limitation was that all the subjects in the HALT-C cohort had received a prior course of therapy that may have influenced liver histology such that patients with IL28B genotype CC with milder disease may have responded to therapy, thereby enriching the cohort with subjects with more severe activity and fibrosis. However, since response to interferon-based therapy is independent of baseline ALT level[31] (a surrogate marker of HAI score), this would likely be true for other IL28B genotypes with milder activity and fibrosis.