Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C

<div><p>The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (<i>IL28B</i>) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable <i>IL28B</i> genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for <i>A20, SOCS1</i>, and <i>SOCS3</i>, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as <i>IRF1</i> were significantly higher at 8 h in patients with an unfavorable <i>IL28B</i> genotype than in those with a favorable one (<i>P</i> = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of <i>IRF1</i> at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable <i>IL28B</i> genotype (<i>P</i> = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to <i>IL28B</i> genotypes, paralleling treatment efficacy.</p></div

Fold-changes of mRNAs including suppressive genes in PBMCs at 8 hours relative to baseline in patients stratified according to <i>IL28B</i> genotype.

<p>TT and TG/GG at rs8099917 is a favorable and an unfavorable <i>IL28B</i> genotype for treatment responses, respectively. Boxes represent the interquartile range of the data. The lines across the boxes and the numbers indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.</p

Associations between the expression of ISGs or IFN-λ3 and treatment efficacy.

<p>Patients were divided into three groups according to <i>IL28B</i> genotype at rs8099917 and treatment outcome: TT; SVR (n = 31), TG/GG; SVR (n = 13), and TG/GG; non-SVR (n = 6). (A) Expression of <i>ISG15, IL28B</i> and suppressive genes in PBMCs at 8 hours after the initial administration of pegylated interferon, ribavirin, plus NS3/4A protease inhibitor in each group. (B) Fold-changes of mRNAs including suppressive genes at 8 hours relative to baseline in each group. Levels of mRNAs including suppressive genes and <i>ISG15</i> were normalized against glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and those for <i>IL28B</i> were measured using the calibration curves of cDNA clone. TT and TG/GG at rs8099917 is a favorable and an unfavorable <i>IL28B</i> genotype for treatment responses, respectively. Boxes represent the interquartile range of the data. The lines across the boxes and the numbers indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.</p

Baseline clinical characteristics of the 50 chronic hepatitis C patients treated with PEG-IFN, RBV and protease inhibitor.

<p>Abbreviations: ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; N.D., not determined; IFN, interferon; RBV, ribavirin; PEG-IFN, pegylated interferon; TVR, transient virological response; NVR, non-virological response.</p><p>rs8099917: TT is favorable for treatment efficacy.</p><p>Data are expressed as numbers for categorical data or the median (range) for continuous data.</p><p>Baseline clinical characteristics of the 50 chronic hepatitis C patients treated with PEG-IFN, RBV and protease inhibitor.</p

Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC? A multicenter study by the Japanese Red Cross Hospital Liver Study Group

<div><p>Background and aim</p><p>This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort.</p><p>Methods</p><p>This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively.</p><p>Results</p><p>AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients.</p><p>Conclusions</p><p>There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.</p></div

HCC cumulative recurrence rate after propensity score matching.

<p>Kaplan-Meier analysis performed after matching also revealed no significant difference between the IFN group (gray line) and the IFN-free DAA group (black line).</p

Baseline patient characteristics.

<p>Baseline patient characteristics.</p

Flow sheet summarizing study selection.

<p>Flow sheet summarizing study selection.</p

Patient characteristics after propensity score matching.

<p>Patient characteristics after propensity score matching.</p

Cumulative hepatocellular carcinoma (HCC) recurrence rate in patients who achieved sustained virological response.

<p>Kaplan-Meier analysis does not show a significant difference between the IFN group (gray line) and IFN-free DAA group (black line).</p