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Background and Aims: Antiviral therapy can stop progression of liver fibrosis and partially reverse it. Non-invasive methods have shown good diagnostic accuracies for the assessment of liver fibrosis. First studies have shown that transient elastography (TE) can be used to monitor fibrosis after antiviral therapy. Acoustic-Radiation-Force-Impulse (ARFI)-Imaging is an elastography method integrated in a conventional ultrasound machine. The aim of the present study was to demonstrate a significant difference of ARFI-values in patients with sustained-virological-response (SVR) as compared to patients without., Method: Ninety-eight patients infected with chronic hepatitis C virus (HCV) who had completed antiviral treatment were prospectively included in the study and received ARFI-imaging, TE and laboratory evaluation., Results: Significantly lower ARFI and TE values were observed for 47 patients with SVR as compared to 51 patients without SVR (1.37 m/s vs. 2.00,p=0.0021; 4.9 kPa vs. 11.1 kPa,p<0.001), respectively., Conclusions: Liver stiffness values and shear wave velocity using ultrasound-based elastography methods are different in patients with SVR as compared to patients without SVR after antiviral therapy for chronic hepatitis C. However, the causes of this difference (fibrosis regression, cytolysis, baseline fibrosis) remain unclear and require further evaluation in future studies.

Background: MicroRNA-122 is a liver specific microRNA and is elevated in the sera of patients with chronic hepatitis C virus infection. Hepatic microRNA-122 levels have been described to be reduced in patients with non-response to antiviral treatment with pegylated interferon-α and ribavirin., Aim: Assessment of differences in serum microRNA-122 levels in patients with sustained virological response and non-response., Methods: RNA was extracted from pretreatment serum samples and microRNA-122 and microRNA-16 levels were measured by quantitative PCR and compared in patients with sustained virological response and non-response., Results: The levels of microRNA-122 and microRNA-16 in the sera did not differ between patients with sustained virological response and non-response., Conclusion: Serum microRNA-122 is not a suitable marker for treatment response prediction to combination therapy with pegylated interferon-α and ribavirin in patients with chronic hepatitis C virus infection., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: More than 180 million people worldwide are infected with the chronic hepatitis C virus (HCV), a major cause of liver cirrhosis, and its life-threatening complications including liver failure, portal hypertension and hepatocellular carcinoma. For patients infected with HCV genotype 1, the chances of a sustained virologic response (SVR) with the previous standard of care treatment (Peg-IFN-α + ribavirin) are only 40 - 50%. Neither drug targets a specific HCV protein, and treatment is not only compromised by insufficient SVR rates but also associated with several side effects. With a better understanding of the HCV life-cycle, and of the structural features of HCV proteins, several promising direct antiviral drugs (DAAs) have entered clinical development., Areas Covered: This review summarizes the clinical development of telaprevir and discusses the possible role of telaprevir in combination with Peg-IFN-α and ribavirin as a new standard treatment against HCV infection, as well as any possible challenges in the future., Expert Opinion: Triple therapy, with telaprevir in combination with Peg-IFN-α + ribavirin, is the new standard for chronic hepatitis C treatment in genotype 1-infected patients. At present, there are several next-generation DAAs in clinical development in combination with Peg-IFN-α. The future, however, may also include new treatment strategies, such as oral DAA combinations.

Treatment for chronic hepatitis C virus (HCV) infection has evolved considerably in the last few years. Combination therapy with pegylated interferon (PEG-IFN)-α plus ribavirin (RBV) has been the standard of care (SoC) treatment in the past few years. Several viral and host factors have been associated with treatment failure, including age, male gender, ethnicity, genotype, IL28B genotype, steatosis, obesity and insulin resistance. Several studies have also shown that in patients who fail treatment, several interferon-stimulated genes are upregulated before treatment. Recently, the NS3/4A protease inhibitors telaprevir and boceprevir have been approved and are considered the new SoC therapy in combination with PEG-IFN-α/RBV in HCV genotype 1 treatment-naïve patients, as well as in previously treated patients, with significant improvements in SVR rates. The REALIZE phase III trial with telaprevir in previously treated patients showed SVR rates of 83-88% in prior relapsers, 54-58% in prior partial responders and, 29-33% in prior non-responders., (© 2012 John Wiley & Sons A/S.)

Objectives: The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection., Methods: RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis., Results: Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA., Conclusions: The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver.

Background & Aims: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection., Methods: Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated., Results: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype., Conclusions: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV., (Copyright © 2011. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.)

Background: MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC., Methodology/principal Findings: 62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = -0.494, P = 0.00002), alanine aminotransferase (ALT) (r = -0.309, P = 0.007), aspartate aminotransferase (r = -0.495, P = 0.000007), bilirubin (r = -0.362, P = 0.002), international normalized ratio (r = -0.338, P = 0.034) and γ-glutamyltransferase (r = -0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dC(T) of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%., Conclusions/significance: The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.

Background/aim: Insulin resistance (IR) is a major predictor of treatment failure in patients with hepatitis C virus (HCV) infection treated with peginterferon/ribavirin. The aim of this study was to evaluate the short-term effect of an HCV protease inhibitor monotherapy on IR in parallel with an antiviral effect., Patients/methods: In a phase 1b placebo-controlled study, four cohorts of treatment-naïve patients with genotype 1 HCV received danoprevir (ITMN-191/RG7227), a protease inhibitor, or placebo (8/2 patients in each cohort respectively) in a gelatin capsule every 12 h (100, 200 mg) or 8 h (100, 200 mg) for 14 days. A fifth cohort including prior non-responders to peginterferon/ribavirin was similarly randomised to receive placebo or 300 mg danoprevir every 12 h. IR was assessed with the homeostasis model (HOMA-IR) at baseline and days 7, 14 and 15., Results: Serum HCV-RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p<0.0001). At baseline, mean±SD serum HCV-RNA level and mean±SD HOMA-IR score were 6.2±0.5 log(10) IU/ml and 3.8±1.9, respectively. At the end of 14 days of monotherapy the mean±SD decrease in viral load was 2.2±1.3 log(10) IU/ml (p<0.0001) in patients who received the active drug (n=40). In parallel, the mean±SD HOMA-IR score also decreased in these patients by 1.6±1.1 (p<0.0001), with a close correlation between the extent of HOMA-IR improvement and the decrease in viral load. By contrast, serum HCV-RNA and HOMA-IR remained unchanged in patients who received placebo (n=10; 6.3±0.5 log(10) IU/ml and 3.8±2.5, respectively)., Conclusion: HCV protease inhibitor may restore insulin sensitivity in patients with genotype 1 HCV. The place of insulin sensitisers remains to be determined in the era of triple therapy.

Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment., Methods: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups., Results: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia., Conclusions: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.), (2009 Massachusetts Medical Society)

Background/aims: The efficacy of pegylated interferon alpha and ribavirin in HBV/HCV co-infected patients is unknown., Methods: Nineteen patients with chronic HBV/HCV co-infection (HBsAg and HCV-RNA positive; 10 HCV-genotype 1; 9 HCV-genotype 2 or 3) were included in this prospective multicenter pilot study. Baseline HBV-DNA was negative in 13 individuals. All patients received weight-adjusted PEG-IFN-alpha2b and ribavirin for 48 weeks., Results: In the intent-to-treat analysis, a biochemical and an HCV-RNA response were observed in 12 and 14 patients, respectively (63% and 74%). At the end of the treatment as well as at the end of the follow-up the HCV-RNA response was 93% (14/15) in patients adherent to therapy (86% in genotype 1 and 100% in genotypes 2 and 3 infection). Two of the five initially HBV-DNA positive patients with follow-up available were HBV-DNA negative at follow-up week 24. In contrast, HBV-DNA became detectable after the clearance of HCV in four initially HBV-DNA negative patients., Conclusions: Combination therapy with PEG-IFN-a2b and ribavirin is highly effective in inducing a virological response concerning HCV in patients with HBV/HCV co-infection. However, HBV replication may increase after the clearance of HCV and thus close monitoring for both the viruses is recommended even in patients with initially undetectable HBV-DNA.

Objective: Neopterin is a marker of monocyte/macrophage activity. Alanine aminotransferase (ALAT) is a marker of hepatocyte injury. The aim of this study was to determine changes in neopterin and ALAT levels, as markers of inflammation, in two ancillary studies during two-phase 1b trials of hepatitis C virus (HCV) NS3.4A protease inhibitor telaprevir (VX-950), with or without peginterferon alfa-2a (Peg-IFN)., Material and Methods: Fifty-four chronic hepatitis C patients (genotype 1) received placebo or telaprevir, with or without Peg-IFN, for 14 days in two multiple-dose studies., Results: During administration of telaprevir, every patient demonstrated a >2-log decrease in HCV RNA. Mean neopterin and ALAT levels decreased in all four groups receiving telaprevir alone. In contrast, mean neopterin levels increased and ALAT levels decreased in the Peg-IFN plus telaprevir and Peg-IFN plus placebo groups., Conclusions: These data suggest that treatment of chronic hepatitis C patients with an HCV NS3.4A protease inhibitor ameliorates inflammation. The increase in neopterin levels and the decrease in ALAT levels during administration of Peg-IFN with or without telaprevir are in accordance with earlier observations showing that IFN reduces hepatocyte injury but increases monocyte/macrophage activity. The IFN-mediated immunomodulatory effects appear to remain intact when IFN is combined with telaprevir.

Unlabelled: Telaprevir (VX-950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (>or=5%), mutations were identified that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon-alpha-2a (PEG-IFN-alpha-2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG-IFN-alpha-2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients., Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild-type virus, which uncovers pre-existing telaprevir-resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG-IFN-alpha-2a inhibited both wild-type and resistant variants. In the present study, every patient who began PEG-IFN-alpha-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive to PEG-IFN-alpha-2a and ribavirin.

Unlabelled: Telaprevir (VX-950), an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, substantially decreased plasma HCV RNA levels in a prior clinical study. The present study evaluated viral kinetics and safety during dosing with telaprevir alone and in combination with peginterferon alfa-2a for 14 days. Previously untreated patients with genotype 1 hepatitis C were randomized to receive placebo and peginterferon alfa-2a (n = 4); telaprevir (n = 8); or telaprevir and peginterferon alfa-2a (n = 8). Telaprevir was given as 750 mg oral doses every 8 hours; peginterferon alfa-2a was given as weekly 180 mug subcutaneous injections. The median change in HCV RNA from baseline to day 15 was -1.09 log(10) (range, -2.08 to -0.46) in the placebo and peginterferon alfa-2a group; -3.99 log(10) (range, -5.28 to -1.26) in the telaprevir group, and -5.49 log(10) (range, -6.54 to -4.30) in the telaprevir and peginterferon alfa-2a group. Day 15 HCV RNA levels were undetectable in 4 patients who received telaprevir and peginterferon alfa-2a and in 1 patient who received telaprevir alone. No viral breakthrough occurred in patients who received telaprevir and peginterferon alfa-2a. The majority of adverse events were mild. There were no serious adverse events or premature discontinuations. Twelve weeks after starting off-study standard therapy, HCV RNA was undetectable in all 8 patients in the telaprevir and peginterferon alfa-2a group, 5 patients in the telaprevir group, and 1 patient in the placebo and peginterferon alfa-2a group., Conclusion: This study confirmed the substantial antiviral effects of telaprevir and showed an increased antiviral effect of telaprevir combined with peginterferon alfa-2a.

Previous studies have shown that the total perihepatic lymph node (PLN) volume is (1) associated with the extent of inflammatory activity in the liver and (2) changes according to the antiviral response in patients receiving interferon-based therapy for chronic hepatitis C (HCV) infection. The aim of this prospective pilot study was to examine whether the total PLN volume similarly changes in patients receiving antiviral monotherapy with the protease inhibitor telaprevir (VX-950). The present study was conducted in a subgroup of 19 patients with chronic hepatitis C genotype-1 infection treated with the protease inhibitor telaprevir (VX-950) or placebo in a phase Ib clinical trial. The total perihepatic lymph node volume was assessed using sonography before the initiation of antiviral therapy, at the end of 14 d of treatment, and at follow-up. Treatment with telaprevir resulted in a significant reduction of plasma HCV-RNA in all patients at the end of 14 d of treatment. In patients receiving telaprevir, the total PLN volume decreased significantly at the end of 14 d of treatment compared with pretreatment volume (1.26 mL to 0.76 mL, p=0.01). In contrast, no significant difference was seen in patients receiving placebo (1.00 mL to 1.06 mL, p=0.26). These results suggest that the perihepatic lymph node volume can be used as an indicator for viral and histologic response not only as previously reported in patients receiving interferon-based therapy, but also in patients receiving therapy with direct antivirals.

Background & Aims: VX-950 specifically inhibits the NS3.4A protease of hepatitis C and has antiviral activity in vitro. This phase I, placebo-controlled, double-blind study evaluated the antiviral activity, pharmacokinetics, and safety of VX-950 in patients with chronic hepatitis C (CHC)., Methods: Thirty-four patients with genotype 1 CHC were randomized to receive placebo or VX-950 at doses of 450 mg or 750 mg every 8 hours or 1250 mg every 12 hours for 14 days. Of the 34 participants, 27 (79%) had failed prior treatment. Patients were monitored for safety and tolerability of VX-950. Plasma VX-950 concentrations and HCV RNA levels were measured., Results: VX-950 was well tolerated and had substantial antiviral effects: viral loads dropped > or =2 log(10) in all 28 patients treated with VX-950 and > or =3 log(10) in 26 (93%) of the 28 patients. In the 750-mg-dose group, which had the highest trough plasma drug concentrations, the median reduction of HCV RNA was 4.4 log(10) after 14 days. In the 450-mg and 1250-mg groups, the maximal effect was seen between days 3 and 7 of dosing, and median HCV RNA increased between days 7 and 14; median reductions at day 14 were 2.4 log(10) and 2.2 log(10), respectively. Median alanine aminotransferase levels decreased during dosing in all VX-950 groups., Conclusions: VX-950 was well tolerated and demonstrated substantial antiviral activity. Some patients had viral breakthrough during dosing, related to selection of variants with decreased sensitivity to VX-950. The results support further studies of VX-950 in patients with CHC.