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Background & Aims: The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection., Methods: Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12)., Results: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components., Conclusions: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patient's organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients., (Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

The known mechanisms of hepatitis C virus (HCV) clearance and their failure in persistent infection are discussed. Interferon-alpha is the main treatment in chronic HCV but has shown poor sustained virological response rates when used as a monotherapy. The effects of interferon-a may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGFbeta, and an effect on HCV induced carcinogenesis. Mathematical modelling studies have provided insights into the mechanisms of action of interferon-alpha in chronic HCV. The two-phase plasma HCV RNA disappearance curve may reflect the presence of an interferon-resistant second site of HCV replication either within or outside the liver. Clinical observations and cerebral magnetic resonance scans provide evidence of functional cerebral impairment in HCV infected patients, raising the issue of the central nervous system (CNS) as a site for HCV replication. Recent studies using ribavirin in combination with interferon suggest that this approach doubles the sustained response rates obtained without having a major effect on the initial rate of HCV clearance (see Zeuzem paper). The potential mechanisms of action of ribavirin, although not yet fully understood, include inhibition of synthesis of GTP by an effect on inosine monophosphate dehydrogenase thereby limiting viral RNA synthesis, and enhancement of TH1 responses, which may assist viral clearance. There is no significant effect on HCV RNA polymerase activity. It is possible that ribavirin may have activity at extrahepatic sites of HCV infection, thus explaining the marked reduction in relapse rates with combination therapy, without an appreciable effect on initial antiviral response.