Latest research on Harvoni

Sofosbuvir is a prodrug nucleotide analog used as part of combination therapy to treat hepatitis C virus (HCV) infection or to treat co-infection of HIV and HCV. After metabolism to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate (also known as GS-461203), the triphosphate serves as a defective substrate for the NS5B protein, an RNA-dependent RNA polymerase required for replication of viral RNA. Sofosbuvir and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid resistance development has proved to be an important cause of therapeutic failure. More recently, sofosbuvir has become available as a fixed dose drug combination product with levipasvir (tradename Harvoni) used for the treatment of chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). Approved in October 2014 by the FDA, ledipasvir and sofosbuvir are direct-acting antiviral agents indicated for the treatment of HCV genotype 1 with or without cirrhosis. HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States affecting 72% of all chronic HCV patients. Prior to development of this drug, the main treatment available was weekly injections of pegylated interferon with weight-based ribavirin over 48 weeks, which achieved a sustained virological response (SVR) of 45-50% and had multiple unpleasant side effects. When combined together, ledipasvir and sofosbuvir have been shown to have a SVR between 93 and 100% after 12 weeks of treatment. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV.

Latest findings

The NIs bind to the active site of the polymerase such as GS-7997, RGB7128, TMC649128, PSI-7977 and PSI-938. [source, 2012]
We have also found 2′-deoxy-2′-fluoro-2′-C-methyluridine-triphosphate, formed by mericitabine [45] and GS-7977 [34], to be an even worse substrate for POLRMT than Ribavirin triphosphate. [source, 2012]
What is known about IFN-free regimens can be summarized as follows: (a) the combination of two oral drugs with a low barrier to resistance results in early virological breakthroughs due to the selection of viral populations that are resistant to both drugs [26-28]; (b) Ribavirin accelerates HCV clearance in combination with direct acting antivirals in the absence of IFN and is useful for shortening treatment duration and preventing post-treatment relapses [27]; (c) the use of a nucleotide analogue (PSI-7977) with Ribavirin in patients infected with HCV genotypes 2 and 3 [29], or of a combination of an NS3-4A protease inhibitor (asunaprevir) and an NS5A inhibitor (daclatasvir) in patients infected with genotype 1b [30], a population in which daclatasvir has a reasonably high barrier to resistance, yielded 100% sustained virological response rates in small groups of patients. [source, 2012]