By Liz Highleyman

Given the limited efficacy and frequent side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection, researchers have explored a variety of targeted oral antiviral agents, including HCV protease and polymerase inhibitors.

Several candidate drugs have demonstrated potent anti-HCV activity in laboratory and clinical trials, but the virus can develop mutations that confer resistance to these agents, especially when used as monotherapy. In addition, some individuals who have never received treatment may harbor HCV strains that are naturally resistant to these antiviral drugs.

As reported in the September 15, 2008 Journal of Infectious Diseases, researchers from Vertex Pharmaceuticals -- which is developing the HCV protease inhibitor telaprevir (VX-950) -- performed an analysis of the prevalence of naturally resistance variants and their effect on clinical response to telaprevir and other experimental HCV protease inhibitors. They conducted a population sequence analysis of the NS3/4A protease in HCV from 570 treatment-naive individuals.

Results

• Most individuals (98%) had wild-type (non-mutated) virus.

• The remaining subjects had the following variants present in significant proportions:

• V36M: 0.9%;

• R155K: 0.7%;

• V170A: 0.2%;

• R109K: 0.2%.

• The V36M, R109K, and V170A substitutions confer low-level resistance (<7-fold) to protease inhibitors in HCV replicons in cell cultures.

• The R155K substitution confers low-level resistance to telaprevir and boceprevir (SCH 503034), and high-level resistance (>70-fold) to BILN 2061 (discontinued due to cardiac toxicity in animal studies) and ITMN-191 (also known as R7227).

• 5 patients with the V36M or R109K variant were treated for 8-24 weeks with telaprevir plus pegylated interferon alfa-2a (Pegasys), with or without ribavirin.

• 4 of the 5 (80%) achieved sustained virological response (the other was lost to follow-up).

• In patients with the R155K variant, the combination of telaprevir/pegylated interferon/ribavirin produced greater antiviral activity than standard therapy with pegylated interferon/ribavirin.

• However, antiviral response to triple therapy was lower in these patients than in individuals with wild-type HCV.

Based on these findings, the study authors concluded, "High levels of naturally occurring protease inhibitor-resistant variants were uncommon (<1% each) in HCV treatment-naive patients."

"[Telaprevir/pegylated interferon/ribavirin] efficiently inhibited V36M and R109K variants and contributed partial antiviral activity against the R155K variant," they added.

Finally, they recommended, "As new HCV agents are evaluated in clinical trials, it will be important to monitor the effect of baseline variants on sensitivity."

9/26/08

Reference
D Bartels, Y Zhou, E Zhang, and others. Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3/4a protease inhibitors in treatment-naive subjects. Journal of Infectious Diseases 198(6): 800-807. September 15, 2008. (Abstract).