Old and emerging therapies in chronic hepatitis C: an update.
ABSTRACT The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response currently defined as undetectable HCV-RNA in peripheral blood determined with the most sensitive polymerase chain reaction technique 24 weeks after the end of treatment. This goal is practically equivalent with eradication of HCV infection and cure of the underlying HCV-induced liver disease. The current standard in hepatitis C treatment consists in combination regimens of pegylated interferon-alpha (Peg-INF-alpha) with Ribavirin (RBV). Such treatment schemes are quite successful in patients with HCV genotypes 2 and 3 infections achieving HCV eradication rates of 75-90%. However, they are much less effective in patients with genotypes 1 and 4 infections with eradication rates ranging between 45% and 52%. Moreover, they have several, and sometimes severe, adverse effects and contraindications, further limiting their efficacy and applicability in an appreciable number of patients with chronic HCV-induced liver disease. Therefore, the need for improvement of existing therapies and for development of new effective, safe and tolerable drugs is a matter of great clinical relevance and importance. In this article, recent improvements in the current standard of therapy with IFN-alpha and RBV in various subsets of patients with chronic hepatitis C and in the clinical development of new emerging drugs, particularly small molecules, will be reviewed and commented. The article is divided in two main parts: (i) improvements in the standard combination therapies and schemes of approved Peg-INF-alpha with RBV and expectations from new interferons, interferon inducers and alternatives to RBV; (ii) new drugs for HCV in clinical development focusing mostly on specific inhibitors of HCV and less so on other drugs including immune therapies.
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ABSTRACT: New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.Stem cell reports. 01/2014; 3(1).
- Human Vaccines - HUM VACCINES. 01/2009; 5(8):568-571.
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ABSTRACT: Depression complicates interferon-based hepatitis C virus (HCV) antiviral therapy in 10% to 40% of cases, and diminishes patient well-being and ability to complete a full course of therapy. As a consequence, the likelihood of achieving a sustained virological response (SVR [ie, permanent viral eradication]) is reduced.OBJECTIVE: To systematically review the evidence of whether pre-emptive antidepressant prophylaxis started before HCV antiviral initiation is beneficial. Inclusion was restricted to randomized controlled trials in which prophylactic antidepressant therapy was started at least two weeks before the initiation of HCV antiviral treatment. Studies pertaining to patients with active or recent depressive symptoms before commencing HCV antiviral therapy were excluded. English language articles from 1946 to July 2012 were included. The MEDLINE, Embase and Cochrane Central databases were searched. Where possible, meta-analyses were conducted evaluating the effect of antidepressant prophylaxis on SVR and major depression as well as on Montgomery-Asberg Depression Rating Scale and Beck Depression Index scores at four, 12 and 24 weeks. The Cochrane Collaboration tool was used to assess bias risk. Six randomized clinical trials involving 522 patients met the inclusion criteria. Although the frequency of on-treatment clinical depression was decreased with antidepressant prophylaxis (risk ratio 0.60 [95% CI 0.38 to 0.93]; P=0.02; I2=24%), no benefit to SVR was identified (risk ratio 1.08 [95% CI 0.74 to 1.57]; P=0.69; I2=58%). This practice is not justified to improve SVR in populations free of active depressive symptoms leading up to HCV antiviral therapy.Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 10/2013; 27(10):575-581.