Simeprevir for the treatment of chronic hepatitis C genotype 1 infection

Abstract

Simeprevir is a second-wave hepatitis C virus NS3/4A protease inhibitor that was designed to optimize its antiviral activity, safety, drug-drug interactions, and pharmacokinetic profile. When used to treat patients with hepatitis C virus genotype 1, simeprevir is coadministered with peginterferon and ribavirin for 12 weeks, followed by double therapy with Peg-IFN and ribavirin for an additional 12 or 36 weeks. Phase III studies achieved a sustained virologic response in 80–90% of treatment-naïve patients (International Phase III studies QUEST-1/2: 80/81%; Japanese Phase III trial CONCERTO-1: 89%). Unlike with the first protease inhibitors, telaprevir or boceprevir, used in triple therapy, when using simeprevir the frequency of clinically problematic adverse events such as anemia, rash, and digestive symptoms is almost comparable to that of double therapy. The advent of simeprevir has enabled interferon therapy, which started as monotherapy in early 1990s, to reach its maximum efficacy and arrive at what can be considered its final form at least in genotype 1b.

Keywords::

• direct acting antiviral
• hepatitis C virus
• peginterferon
• protease inhibitor
• Simeprevir

Financial & competing interests disclosure

T Takehara has received research grants and lecturer fees from MSD, Chugai, Bristol-Myers Squibb, Mitsubishi Tanabe Pharma, and Janssen Pharmaceutical Company. The author has no other 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 apart from those disclosed.

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

Key issues

• Simeprevir (SMV) is a second-wave hepatitis C virus NS3/4A protease inhibitor that was designed to optimize its antiviral activity, drug–drug interactions and pharmacokinetics.

• SMV is coadministered with peginterferon (Peg-IFN) and ribavirin (RBV) for 12 weeks, followed by double therapy with Peg-IFN and RBV for an additional 12 or 36 weeks for genotype 1 patients.

• SMV + Peg-IFN + RBV therapy yields a high sustained virologic response rate (≥80%) for treatment-naive patients.

• The efficacy of SMV + Peg-IFN + RBV therapy depends on factors such as responsiveness to IFN (IL28B genotypes for naive patients or responsiveness to prior treatment for experienced patients) and the stage of liver fibrosis.

• Therapeutic efficacy of triple therapy with SMV is slightly lower in genotype 1a patients than in genotype 1b patients due to the Q80K mutation seen in a proportion of genotype 1a patients.

• In patients who developed virological failure to SMV + Peg-IFN + RBV therapy, mutation can develop specifically D168V for genotype 1b and R155K for genotype 1a, which may have little influence to give the effect of the later therapy such as a combination of NS5A inhibitor and NS5B inhibitor.

Notes