Hep C Discussion Forum

Gilead's exploration is ongoing re: RAVS and development of using of other possible alternate NS5B drugs like SOF and GS-9190 in combo therapies.

Early trials on GS-9190, comparing classes of a "non-nucleoside inhibitor" (NNI) and "nucleoside inhibitors" (NI's) in newer DAA double and triple therapies, as compared to SOF being used in newer double/triple DAA therapies.

Journal of Viral Hepatitis

Antiviral Response and Resistance Analysis of Treatment-naïve HCV-infected Patients Receiving Single and Multiple Doses of GS-9190

H. Mo; C. Hedskog; E. Svarovskaia; S.-C. Sun; I. M. Jacobson; D. M. Brainard; J. G. McHutchison; M. D. Miller

Disclosures

J Viral Hepat. 2016;23(8):644-651. 

... In the last several years, there has been expansion in development of direct-acting antiviral agents (DAAs) for treatment of chronic HCV infection. By combining two or more DAAs, high rates of sustained virologic response (SVR) have been achieved. Similar to other RNA viruses, HCV exists as a highly genetically diverse population within infected individuals.^[2] HCV's RNA-dependent RNA polymerase lacks proofreading ability and generates approximately 10^3-10⁵ nucleotide mutations per replication cycle.^[3]Accordingly, mutations conferring resistance to DAAs have been shown to pre-exist in the viral population and to be rapidly selected during monotherapy with NS3 or NS5A inhibitors.^[4] Similar observations have been made with the class of non-nucleoside analogue (NNI) inhibitors of NS5B.^[5] In contrast, resistance to nucleoside analogue inhibitors (NI) of NS5B is less frequent.^[6]

The viral NS5B enzyme is an attractive target for drug development, where NIs target the highly conserved NS5B active site and NNIs target one of the four allosteric binding sites that are located within the thumb and palm domain of the protein.^{[7,8] Cu}rrently, there is one NI and one NNI approved on the market, sofosbuvir (SOF) and dasabuvir, respectively.