Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C

Abstract

MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.

Fig. 1.

Pretreatment serum miR-122 level is associated with treatment response. (A) A significantly higher pretreatment serum miR-122 level was found among patients who showed cEVR and SVR, but not RVR. (B) The pretreatment serum miR-122 level was significantly higher in patients of genotype 2 compared with genotype 1 in terms of cEVR and SVR. Box plot (25th–50th–75th quartile) with whiskers (lower and upper extremes) and outliers demonstrated.

Fig. 2.

Association of pretreatment serum miR-122 level with IL-28B genotypes. (A) A significant trend of higher miR-122 level was found among patients with IL-28B TT genotype compared with GT and GG genotypes (9.52 vs. 9.35 vs. 8.78 log₁₀ copies per milliliter ; P = 0.014 for trend). (B) A significantly higher serum miR-122 level was found between cEVR and SVR patients of IL-28B TT genotype but not in GT/GG genotypes. Box plot (25th–50th–75th quartile) with whiskers (lower and upper extremes) and outliers demonstrated.

Fig. 3.

Longitudinal analysis of serum miR-122 level during pegIFN/RBV therapy. (A) Line plot of individual serum miR-122 profiles from week 0, 4, 8, 12, 24, 48, or 72 by treatment responses: SVR vs. NR. (B) Predicted values (with 95% CI) of serum miR-122 levels during therapy by repeated-measures mixed-model analysis (P < 0.0001, SVR vs. NR). No significant dynamic change was observed after therapy.