Asunaprevir-containing regimens for the treatment of hepatitis C virus infection

Abstract

Chronic hepatitis C virus (HCV) infection has been a tremendous health burden worldwide with an annual mortality of 300,000 people due to decompensated cirrhosis or hepatocellular carcinoma. A combination of interferon (IFN), ribavirin (RBV), and/or direct-acting antivirals (DAAs) can eradicate HCV in a various proportion of infected patients. Unfortunately, IFN-based therapy is associated with significant adverse effects, contraindications, and limited tolerability, leading to lower adherence or even treatment discontinuation. With the rapid evolution of newer DAAs or host-targeting agents, emerging HCV therapy is moving towards an IFN- and RBV-free strategy. To this end, a recently developed NS3 protease inhibitor, asunaprevir (ASV), in combination with other DAAs as IFN/RBV-containing or -free regimen, has shown promising results with fewer adverse effects. In this review, preclinical profiles and clinical proof-of-concept studies of ASV, including viral resistance, host polymorphism, and role of ASV in future HCV therapy are reviewed and discussed.

Keywords:

• asunaprevir
• direct-acting antivirals
• hepatitis C virus
• interferon
• NS3 protease inhibitor
• 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

• Chronic hepatitis C virus (HCV) infection remains a global health burden caused by disease-associated morbidity and mortality.

• Current interferon (IFN) plus ribavirin (RBV) based therapy is able to eradicate HCV from the infected host with response rate varied to ethics, host and viral factors.

• Two direct-acting antivirals classified as first-generation NS3/4A protease inhibitors, boceprevir and telaprevir, had been approved in combination with IFN and RBV for treating HCV genotype 1 in many countries since May 2011. Pill burden and worsened adverse effects are their major disadvantages.

• Simeprevir, a second-generation NS3/4A protease inhibitor, in combination with IFN and RBV has been approved to treat HCV genotype 1, 2, 5, 6 by US FDA in the end of 2013.

• Sofosbuvir, a potent nucleotide NS5B polymerase inhibitor, has been approved by the FDA in the end of 2013 for treating HCV genotype 1, 2, 3 or 4 patients including chronic hepatitis C (CHC) patients with hepatocellular carcinoma within Milan criteria awaiting liver transplantation and those with HCV/HIV-1 coinfection as a component of combination regimen with or without IFN.

• Emerging newer direct-acting and host-targeting antivirals in combinations with IFN- and RBV-free or in shape of fix-dose compound will change HCV therapy profoundly in the future.

• Asunaprevir (ASV), a second-generation NS3 protease inhibitor developed by Bristol-Myers Squibb, should be used as a component of combination regimen with other NS5A replication complex inhibitor or NS5B polymerase inhibitor with or without IFN and RBV for CHC genotype 1 naïve or previous treatment failure patients including those with cirrhosis.

• ASV should not be used as monotherapy for HCV treatment.

• The potential role of ASV in combination with other direct-acting antivirals for treating HCV genotype 1 or 4 infected subpopulations such as decompensated cirrhosis or hepatocellular carcinoma awaiting liver transplantation, coinfected with HIV-1, severe renal impairment or end stage renal disease under hemodialysis, liver and/or renal transplant recipients requires further studies.

• Clinical trials on ASV-containing regimens to treat HCV genotype 4 infected patients are currently underway.

• The FDA has granted its investigational daclatasvir dual regimen (ASV and daclatasvir) Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b CHC infection in February 2014.

• ASV in combination with daclatasvir has been approved in Japan to treat HCV genotype 1b CHC patients in July 2014.