Ombitasvir: a potent pan-genotypic inhibitor of NS5A for the treatment of hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) chronically infects about 150,000,000 people worldwide and is a relevant cause of liver cirrhosis, hepatocellular carcinoma and death. Antiviral treatment is rapidly moving from interferon (IFN)-based therapy to IFN-free approaches. This review focuses on the mechanism of action, pharmacokinetics, efficacy, tolerability, safety and resistance of ombitasvir, which is an inhibitor of the HCV nonstructural protein 5A. The pharmacokinetics of ombitasvir enables its once daily administration. In vivo, in combinations with other oral direct acting antivirals, ombitasvir achieves very high rates of sustained virological response (about 95%) in patients with HCV genotype 1 infection with a good tolerability. Resistance profiling revealed a low barrier to resistance when given as monotherapy. However, coadministration of ombitasvir and other antivirals enhances its barrier to resistance. In conclusion, ombitasvir is a good drug to be used in IFN-free combinations for the treatment of chronic hepatitis C.

Keywords::

• ABT-450
• dasabuvir
• interferon-free
• NS5A
• ombitasvir
• pegylated-interferon
• resistance
• ribavirin

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this Manuscript.

Key issues

• Ombitasvir is an inhibitor of the HCV NS5A protein that plays a key role in viral replication and virion assembly.

• In vitro, ombitasvir is a powerful antiviral against different HCV genotypes (1, 2, 3, 4 and 5) with an EC₅₀ ranging from 1.71 to 19.3 pM.

• In vitro, ombitasvir exerts a synergistic effect with the protease inhibitor ABT-450 and the non-nucleoside NS5B inhibitor dasabuvir.

• The optimal pharmacokinetics (half-life of 18–32 h) allows for one administration daily.

• In vivo, in genotype 1-infected patients ombitasvir monotherapy causes a 3-log drop in viral load.

• In Phase III trials, ombitasvir associated with ABT-450/ritonavir, dasabuvir and ribavirin is associated with a very high rate of viral clearance (about 95%).

• Tolerability and the safety profile of ombitasvir are optimal.

• Ombitasvir’s resistance barrier is low, especially for subtype 1a, like all NS5A inhibitors. Mutations appear after only 2 days of monotherapy, but the association with other antivirals increases the resistance barrier.