Source: DGNews  |  Posted 3 years ago

By Em Brown

SAN FRANCISCO -- November 3, 2008 -- Patients with chronic hepatitis C virus (HCV) infection who have responded poorly to standard antiviral treatment in the past may get a bump in viral response rates if the antidiabetic agent and insulin sensitiser metformin is added to pegylated interferon (PEG-IFN) alfa-2a and ribavirin, according to findings presented at the Liver Meeting 2008, the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

The late-breaking clinical trial results were described here on November 2 in a special presentation of research highlights, moderated by AASLD President Arthur J. McCullough, MD, Case Western Reserve University, Cleveland, Ohio.

The prospective, multicentre, double-blinded, placebo-controlled trial (TRIC-1), led by Manuel Romero-Gomez, MD, Hospital Universitario de Valme, Seville, Spain, involved 125 consecutive patients with chronic HCV genotype 1 infection and insulin resistance, who were randomised to receive either metformin 425 mg 3 times a day during the first month, followed by metformin 850 mg 3 times a day from weeks 4 to 48, or placebo. All subjects were also given standard therapy with PEG-IFN alfa-2a 180 mcg weekly and ribavirin 1,000 to 1,200 mg daily.

Baseline characteristics were similar between the study group and controls. The mean age was 47 years (+- 8 years) in the metformin group and 48 years (+- 8 years) in the placebo group. Baseline viral load was 6.33 log₁₀ IU/mL (+- 0.73 log₁₀ IU/mL) in the study group and 6.48 log₁₀ IU/mL (+- 0.76 log₁₀ IU/mL) in controls.

Virological response was assessed at 4, 12, 24, and 72 weeks in an intention-to-treat analysis.

Dr. Romero-Gomez reported that at week 12, viral clearance had occurred in 54.2% of metformin-treated patients compared with 48.4% of controls. At 24 weeks, 74.6% and 75% of patients showed viral clearance in the 2 groups, respectively. At 72 weeks, the sustained viral response (SVR) rates were 52.5% with metformin and 42.2% without it.

Women (n = 54) showed a stronger response to the addition of metformin than men, with viral clearance at week 12 occurring in 57.7% of women compared with 39.3% of men. At week 24, 80.8% of women and 71.4% had viral clearance and SVR rates at 72 weeks were 57.7% in women and 28.6% of men (P = .031).

"Viral load decreased during the first 12 weeks in a gender-dependent manner," Dr. Romero-Gomez noted. Viral load dropped 4.18 log₁₀ IU/mL (+- 1.18 log₁₀ IU/mL) in women and dropped 4.02 log₁₀ IU/mL (+- 1.68 log₁₀ IU/mL) in men (P = .044).

Triple therapy was well tolerated, the investigators reported. Adverse effects were largely gastrointestinal, particularly mild diarrhoea, occurring in 34.1% of patients on metformin and 11.4% of patients on PEG-IFN alfa-2a alone (P < .05).

Metformin demonstrated a greater response among women who were heavier than among those who were leaner; however, "these patients were not particularly heavy, overall," explained Dr. McCullough during the special presentation.

"Many patients with chronic HCV infection have insulin resistance," noted Dr. McCullough. "Fat in the liver inhibits response to antiviral therapy. Increasing insulin sensitivity should improve response to treatment."

Results demonstrated that insulin sensitivity increased in patients receiving metformin, but not in those given placebo.

"Women have more fat stores," Dr. McCullough explained. "Metformin improves their response, but at 57.7%, response rates are still low, overall."

Funding for this study was provided by F. Hoffmann-La Roche Ltd.

[Presentation title: Metformin With Peginterferon Alfa-2a and Ribavirin in the Treatment of Naïve Genotype 1 Chronic Hepatitis C Patients With Insulin Resistance (TRIC-1): Final Results of a Randomized and Double-Blinded Trial. Abstract LB6]