Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C.

Abstract

BACKGROUND/AIM:

Insulin resistance (IR) is a major predictor of treatment failure in patients with hepatitis C virus (HCV) infection treated with peginterferon/ribavirin. The aim of this study was to evaluate the short-term effect of an HCV protease inhibitor monotherapy on IR in parallel with an antiviral effect.

PATIENTS/METHODS:

In a phase 1b placebo-controlled study, four cohorts of treatment-naïve patients with genotype 1 HCV received danoprevir (ITMN-191/RG7227), a protease inhibitor, or placebo (8/2 patients in each cohort respectively) in a gelatin capsule every 12 h (100, 200 mg) or 8 h (100, 200 mg) for 14 days. A fifth cohort including prior non-responders to peginterferon/ribavirin was similarly randomised to receive placebo or 300 mg danoprevir every 12 h. IR was assessed with the homeostasis model (HOMA-IR) at baseline and days 7, 14 and 15.

RESULTS:

Serum HCV-RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p<0.0001). At baseline, mean±SD serum HCV-RNA level and mean±SD HOMA-IR score were 6.2±0.5 log(10) IU/ml and 3.8±1.9, respectively. At the end of 14 days of monotherapy the mean±SD decrease in viral load was 2.2±1.3 log(10) IU/ml (p<0.0001) in patients who received the active drug (n=40). In parallel, the mean±SD HOMA-IR score also decreased in these patients by 1.6±1.1 (p<0.0001), with a close correlation between the extent of HOMA-IR improvement and the decrease in viral load. By contrast, serum HCV-RNA and HOMA-IR remained unchanged in patients who received placebo (n=10; 6.3±0.5 log(10) IU/ml and 3.8±2.5, respectively).

CONCLUSION:

HCV protease inhibitor may restore insulin sensitivity in patients with genotype 1 HCV. The place of insulin sensitisers remains to be determined in the era of triple therapy.

• Authors: Rami Moucari, Nicole Forestier, Dominique Larrey, Dominique Guyader, Patrice Couzigou, Yves Benhamou, Hélène Voitot, Michel Vidaud, Scott Seiwert, Bill Bradford, Stefan Zeuzem, Patrick Marcellin
• Journal: Gut (Gut) Vol. 59 Issue 12 Pg. 1694-8 (Dec 2010) ISSN: 1468-3288 [Electronic] England
• PMID: 20861007 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Cyclopropanes
• Isoindoles
• Lactams
• Lactams, Macrocyclic
• NS3 protein, hepatitis C virus
• Protease Inhibitors
• RNA, Viral
• Sulfonamides
• Viral Nonstructural Proteins
• danoprevir
• Proline

Topics

• Adult
• Antiviral Agents (therapeutic use)
• Cyclopropanes
• Female
• Genotype
• Hepacivirus (genetics, isolation & purification)
• Hepatitis C, Chronic (drug therapy, physiopathology, virology)
• Humans
• Insulin Resistance (physiology)
• Isoindoles
• Lactams (therapeutic use)
• Lactams, Macrocyclic
• Male
• Middle Aged
• Proline (analogs & derivatives)
• Protease Inhibitors (therapeutic use)
• RNA, Viral (blood)
• Sulfonamides (therapeutic use)
• Viral Load (physiology)
• Viral Nonstructural Proteins (antagonists & inhibitors)