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: To evaluate the effects of fucoidan, a complex sulfated polysaccharide extract from marine seaweed, on hepatitis C virus (HCV) RNA load both in vitro and in vivo. HCV-1b replicon-expressing cells were cultured in the presence of fucoidan obtained from Cladosiphon okamuranus Tokida cultivated in Okinawa, Japan, and quantified the level of HCV replication. In an open-label uncontrolled study, 15 patients with chronic hepatitis C, and HCV-related cirrhosis and hepatocellular carcinoma were treated with fucoidan (0.83 g/d) for 12 mo. The clinical symptoms, biochemical tests, and HCV RNA levels were assessed before, during, and after treatment. Fucoidan dose-dependently inhibited the expression of HCV replicon. At 8-10 mo of treatment with fucoidan, HCV RNA levels were significantly lower relative to the baseline. The same treatment also tended to lower serum alanine aminotransferase levels, and the latter correlated with HCV RNA levels. However, the improved laboratory tests did not translate into significant clinical improvement. Fucoidan had no serious adverse effects. Our findings suggest that fucoidan is safe and useful in the treatment of patients with HCV-related chronic liver diseases. Further controlled clinical trials are needed to confirm the present findings.World Journal of Gastroenterology 05/2012; 18(18):2225-30. · 2.55 Impact Factor
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ABSTRACT: Global prevalence of Hepatitis C Virus (HCV) infection corresponds to about 130 million HCV positive patients worldwide. The only drug that effectively reduces viral load is interferon-α (IFN-α) and currently combination of IFN and ribavirin is the choice for treatment. The present study is aimed to resolve the genotypes based on core gene that might affect the response to interferon therapy. Furthermore an attempt was made to propose a powerful therapeutic approach by designing the siRNA from sequences of the same patients who remain resistant to IFN in this study. To achieve the objectives, a sequence analysis was performed in five HCV ELISA positive subjects who have completed IFN treatment. Neighbor Joining (NJ) method was used to study the evolutionary relationship. Atomic models were predicted using online software PROCHECK and i- TASSER. Two new genotypes were reported for the first time namely 4a from suburban region of Rawalpindi and 6e from all over the Pakistan. According to Ramachandran plot, satisfactory atomic model was considered useful for further studies, i.e. to calculate HCV genotypes conservation at structural level, to find out critical binding sites for drug designing, or to silence those binding sites by using appropriate siRNA. Single siRNA can be used to inhibit HCV RNA synthesis against genotype 3 and 4, as the predicted siRNA were originated from the same domain in studied HCV core region in both genotypes. We can conclude that any change or mutation in core region might be the cause of HCV strains to resist against IFN therapy. Therefore, further understanding of the complex mechanism involved in disrupting viral response to therapy would facilitate the development of more effective therapeutic regimens. Additionally, a single designed siRNA can be used as an alternative for current therapy against more than one resistant HCV genotypes.Hepatitis Monthly 06/2012; 12(6):398-407. · 1.25 Impact Factor
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ABSTRACT: Interferon alpha linked to apolipoprotein A-I has been recently proposed as an improved interferon-based therapy. In the present study, we aimed to develop a computational model to gain further insight into the in vivo behaviour of this new fusion protein. In order to facilitate in vivo evaluation of interferon and the fusion protein without altering their biological properties, green fluorescent protein was incorporated into their structures. Kinetic and dynamic behaviour of both compounds was successfully described after plasmid hydrodynamic administration and in situ synthesis of the studied proteins. Results from the modelling exercise showed that apolipoprotein A-I conferred a modified kinetic behaviour, varying molecule distribution and prolonging half-life without altering liver dynamic performance. However, differences in the gene expression activity were observed at brain level between both compounds. Those differences could be explained by modifications in the dynamic, but also in the biodistribution properties, which would be worth evaluating in future experiments. Therefore, the modelling approach provided a global comprehension of a complex system and allowed us to compare the in vivo behaviour of both compounds and to identify critical aspects that might be important to understand the system better and suggests a need for new model-based experiments.PLoS ONE 01/2012; 7(7):e42100. · 3.73 Impact Factor