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

These new drugs can be used in well tolerated all oral, interferon-free regimens, such as sofosbuvir/ledipasvir (Harvoni, Gilead) and Viekira Pak (AbbVie). [source, 2016]
Sofosbuvir (GS-7977, Fig. 2A)6, 7 is a nucleotide analog that inhibits HCV NS5B polymerase. [source, 2016]
On December 6, 2013, FDA approved sofosbuvir (brand name: Sovaldi) for use in the treatment of chronic hepatitis C, genotypes 1, 2, 3 and 4, in combination with PEG-IFN and RBV, or with RBV alone (depending on the genotype). [source, 2016]
Harvoni (sofosbuvir+ledipasvir; GS7977+GS-5855) is a fixed-dose combination tablet containing ledipasvir (90 mg) and sofosbusvir (400 mg) for oral administration. [source, 2016]
The efficacy of Harvoni against HCV genotype 1 was demonstrated in three phase III trials in which SVR rates of 93%–99% were achieved after 12 weeks of therapy. [source, 2016]
The US FDA approved Harvoni to treat chronic HCV genotype 1 infection on October 10, 2014. [source, 2016]
The anti-HCV activities of the synthesized hit compounds were then evaluated using the HCV cell culture system, with PSI-7977 [90] and telaprevir [91] as positive control. [source, 2016]
Initially the antiviral potency of a mixture of PSI-7977 diastereomers was evaluated, but it was later discovered that a purified non-racemic single diastereomer produced significantly greater reductions in HCV RNA. [source, 2015]
This compound, PSI-7977, is now known as sofosbuvir and allows for once-daily dosing and the potential for generating high concentrations of the active triphosphate in the liver. [source, 2015]
Gilead Sciences acquired Pharmasset Inc. and PSI-7977 in November of 2011 and conducted additional preclinical and clinical research to evaluate the pharmacology and clinical safety and efficacy (Phase 2b and 3) of sofosbuvir, the results of which are summarized here. [source, 2015]