HBV-miR-3 is closely related to HBV replication and strongly predictive of HBeAg seroconversion in PegIFN-α treated patients

Abstract

HBV-miR-3 is encoded by HBV and takes part in pathogenesis of HBV-related liver disease. Whether HBV-miR-3 has a relationship with HBV replication and is predictive of PegIFN-α treatment response is still unknown. HBV-miR-3 quantification is based on qRT-PCR. The relationship of HBV-miR-3 and HBV replication, and predictive value of HBV-miR-3 were evaluated in a cohort of 650 HBeAg positive patients from a multi-center, randomized phase III clinical trial for the study of PegIFN-a2b. HBV-miR-3 is significantly positively related to HBVDNA, HBVpgRNA, HBeAg and HBsAg at baseline and at all the different time points during PegIFN-α treatment. Both univariate regression analyses and multivariate logistic regression analyses showed HBV-miR-3 is a predictor of HBeAg seroconversion in the patients treated with PegIFN-α at weeks of 0, 12, and 24. 70.0% of patients with HBV-miR-3 < 3log at week 12 achieved HBeAg seroconversion, otherwise, with HBV-miR-3 > 6log at week 12 no patient obtained HBeAg seroconversion. Conbination of HBV-miR-3 and HBeAg is more strongly predictive of HBeAg seroconversion (83.64%) at week 12. HBV-miR-3 is new biomarker for HBV replication and positively correlated to HBV replication. HBV-miR-3 is also an early predictor of HBeAg seroconversion in the patients treated with PegIFN-α.

Figure 1

HBV biomarkers dynamic changes between the HBeAg seroconversion group and the Non-HBeAg seroconversion group. (A) Spearman correlation coefficient in the pairwise correlations between HBV-miR-3, HBV RNA, HBV DNA, HBsAg, and HBeAg at different time-points. (B) Relationship Between HBV-miR-3 and HBV Replication: HBV-miR-3, HBV DNA, and HBV pgRNA in HepG2 versus HepG2.2.15 cells and HepG2 cells versus HepG2 cells transfected with pHBV1.3 plasmid. (C) Dynamic changes of HBV-miR-3, HBV RNA, HBV DNA and HBeAg during PegIFN treatment. (D) Differences in HBV-miR-3 between the HBeAg seroconversion group and the Non-HBeAg seroconversion group at different time-points. (E) HBV-miR-threefold changes at 12, 24, and 36 weeks to baseline in HBeAg seroconversion and non-seroconversion groups.

Figure 2

HBV-miR-3 is an early predictor for HBeAg seroconversion in the HBeAg-positive patients treated with PegIFN-α. (A) AUC values of HBV-miR3 at weeks 0 and 12. (B)Predictive performance of biomarker cut-off values and their combined performance. (C)Substrate analysis of HBV-miR3 level for the PegIFN-a response.