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


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).


CONCLUSIONS
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.
Moucari
Rami
R
Service d'Hépatologie et INSERM U773-CRB3, Hôpital Beaujon, Clichy, France. rmoucari@yahoo.com
Forestier
Nicole
N
Larrey
Dominique
D
Guyader
Dominique
D
Couzigou
Patrice
P
Benhamou
Yves
Y
Voitot
Hélène
H
Vidaud
Michel
M
Seiwert
Scott
S
Bradford
Bill
B
Zeuzem
Stefan
S
Marcellin
Patrick
P
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D003521:Cyclopropanes; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D054833:Isoindoles; D007769:Lactams / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D013449:Sulfonamides / Q000627:therapeutic use*; D019562:Viral Load / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011392:Proline; D011480:Protease Inhibitors; D012367:RNA, Viral; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir