IFI35, mir-99a and HCV Genotype to Predict Sustained Virological Response to Pegylated-Interferon Plus Ribavirin in Chronic Hepatitis C

Abstract

Although, the treatment of chronic hepatitis C (CHC) greatly improved with the use of direct antiviral agents, pegylated-interferon (PEG-IFN) plus ribavirin remains an option for many patients, worldwide. The intra-hepatic level of expression of interferon stimulated genes (ISGs) and the rs12979860 CC genotype located within IFNL3 have been associated with sustained virological response (SVR), in patients with CHC. The aim of the study was to identify micro-RNAs associated with SVR and to build an accurate signature to predict SVR. Pre-treatment liver biopsies from 111 patients, treated with PEG-IFN plus ribavirin, were studied. Fifty-seven patients had SVR, 36 non-response (NR) and 18 relapse (RR). The expression of 851 human miRNAs and 30 selected mRNAs, including ISGs, was assessed by RT-qPCR. In the first group of patients (screen), 20 miRNAs out of the 851 studied were deregulated between NRs and SVRs. From the 4 miRNAs validated (mir-23a, mir-181a*, mir-217 and mir-99a), in the second group of patients (validation), 3 (mir-23a, mir-181a* and mir-99a) were down-regulated in NRs as compared to SVRs. The ISGs, studied, were accumulated in SVRs and IFNL3 rs12979860 CT/TT carriers compared respectively to NRs and CC carriers. Combining, clinical data together with the expression of selected genes and micro-RNAs, we identified a signature (IFI35, mir-99a and HCV genotype) to predict SVR (AUC:0.876) with a positive predictive value of 86.54% with high sensibility (80%) and specificity (80.4%). This signature may help to characterize patients with low chance to respond to PEG-IFN/ribavirin and to elucidate mechanisms of NR.

Serum and exosomal miR‐122 and miR‐199a as a biomarker to predict therapeutic efficacy of hepatitis C patients

“…Although serum miR‐122 levels correlated with changes in HCV levels across all genotypes, miR‐122 was significantly higher in HCV genotype 1b patients than in non‐genotype 1b patients in our study, indicating that the viral genotype might be a key factor that provokes changes in miRNA expression . Our results reveal that serum miR‐122 levels are closely related to therapy outcomes, suggesting that miR‐122 expression correlate with the treatment response . Lower expression of miR‐199a was significantly correlated with the malignancy potential and poor prognosis of human HCC, which may correlate with a different pathway cascade .…”

“…6 Our results reveal that serum miR-122 levels are closely related to therapy outcomes, suggesting that miR-122 expression correlate with the treatment response. [24][25][26] Lower expression of miR-199a was significantly correlated with the malignancy potential and poor prognosis of human HCC, which may correlate with a different pathway cascade. 27 In our study, the miR-199a level in serum in the SVR group was significantly higher than that in the NR group.…”

MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C

“…RNA was precipitated, and washed in 80% Et-OH. The pellet was dissolved in RNase and DNase free H 2 O 60 . Optical density of total RNA was measured at 260 nm.…”

“…Total RNAs were extracted from 400 μl of serum (MiRvana, Life science). Since there is no reliable serum miRNA stably expressed in the serum, 5.6 × 10 8 copies of Caenorhabdditis elegans miR-39 (cel-miR-39, Qiagen) was added to each serum sample before the extraction 20 60 .…”

“…Briefly, 1 ng of the reverse transcription product was used to assess the expression of each miARNs. The expression of hepatic microRNAs was normalized to the amount of a control small RNA, SNORD44 20 60 whereas the amount of serum microRNAs was normalized to the amount of the spiked-in cel -miR-39.…”