cùng nhau với lõi HCV (Shi 2002). May NS5A cũng hoạt động như một kênh để bảo vệ Điều đó giúp đỡ và RNA virus trực tiếp Trong thời hạn màng của phức Replication (Tellinghuisen 2005). | 66 Hepatitis C Guide gether with the HCV core Shi 2002 . NS5A may also serve as a channel that helps to protect and direct viral RNA within the membranes of the replication complex Tellinghuisen 2005 . Moreover it was demonstrated that NS5A is able to interact with NS5B which results in an enhanced activity of the HCV RNA polymerase. Besides its regulatory impact on HCV replication NS5A has been shown to modulate host cell signaling pathways which for example has been associated with interferon resistance Wohnsland 2007 . Furthermore mutations within the NS5A protein have been clinically associated with resistance I sensitivity to IFN-based antiviral therapy Wohnsland 2007 . BMS-790052 was the first NS5A inhibitor to be evaluated clinically. BMS-790052 monotherapy leads to a sharp initial decline of HCV RNA concentrations though its genetic barrier to resistance is relatively low Gao 2010 . According to an interim analysis treatment with BMS-790052 in combination with PEG-IFN a and ribavirin results in RVR and cEVR rates in over 80 of patients. Importantly BMS-790052 displays a high antiviral activity against most HCV genotypes. Combination therapies of specific antivirals It is a fundamental question whether an SVR can be achieved with combination therapies of different DAA compounds without PEG-IFN a and ribavirin. A first clinical trial INFORM-1 evaluated the combination of a polymerase inhibitor Mericit-abine R7128 and a NS3 inhibitor R7227 ITMN191 . In this proof of principle study patients were treated with both compounds for up to 2 weeks. HCV RNA concentrations decreased up to log10 IU ml viral breakthrough was observed in only one patient but no resistant HCV variants were identified and HCV RNA was undetectable at the end of dosing in up to 63 of treatment-naive patients Gane 2010 . Several tri Thisg i serial 5. New Agents for Treating Hepatitis C 67 mens including NS3 protease inhibitors nucleoside and non-nucleoside NS5B .
