Fat Gets in the Way of Hepatitis C Therapy

ROCHESTER, Minn., June 2 ? Obesity and hepatitis C infection act as a one-two punch on the liver, but treating the obesity may also improve the efficacy of antiviral therapy, reported researchers here.

In a review of the effects of obesity on antiviral therapies for hepatitis C (HCV) infection, a Mayo Clinic team found evidence that points to control of obesity as an important therapeutic adjunct.

"Patients who have chronic hepatitis C and are obese are more likely to be insulin-resistant and to have more advanced hepatic steatosis/steatohepatitis and fibrosis," wrote Michael R. Charlton, M.D., and colleagues, in the June issue of Hepatology.

"These latter conditions are independent predictors of non-response to combination therapy with peginterferon alpha and ribavirin [Rebetol], and obese patients are therefore more likely to be non0responders to combination therapy."

"Treatment strategies that focus on improving underlying metabolic factors associated with poor response to combination therapy are thus more likely to overcome the low sustained virologic response," wrote Dr. Charlton and colleagues.

According to the National Health and Nutrition Examination Survey (NHANES) III, about 2.7 million American have chronic HCV infections. Of this population about 20% are obese, putting them at increased risk for steatosis and the progression of fibrosis, the authors noted.

They explored some of the mechanisms whereby obesity and its consequence, the metabolic syndrome, may interfere with antiviral therapies directed against HCV.

For example, among patients with metabolic syndrome, which is associated with non-alcoholic fatty-liver disease, those who also have chronic HCV infections are significantly more likely to develop advanced liver disease than those who are free of HCV infection, and obese patients with chronic HCV are at a greater risk of developing co-existent steatosis and more advanced liver disease.

"Whereas both viral and host factors contribute to coexistent steatosis, clinical factors associated with the metabolic syndrome--including elevated waist-to-hip ratio, the presence of insulin resistance, and diabetes--have been shown to predict more advanced forms of chronic hepatitis C," the investigators wrote.

Obesity also appears to interfere, through a variety of mechanisms, with the efficacy of pegylated interferons plus Rebetol, which is the current gold standard for treating HCV infections, the authors noted.

Three main hypotheses have been proposed to explain how obesity may dampen the effect of antiviral therapy, the authors noted:

• Because obesity is an inflammatory condition, it is associated with the release of pro-inflammatory cytokines that may alter the immune response to therapy
• Insulin resistance and hepatic steatosis associated with obesity lead to steatohepatitis and hepatic fibrosis, which may in turn interfere with the action of interferons on hepatocytes.
• High levels of subcutaneous fat in obese patients may impair absorption of peginterferon alpha by altering lymphatic uptake of the drug, thereby reducing its bioavailability in serum.

The evidence points to control of obesity as an important adjunct to treatment of HCV, the authors said.

"In formulating more effective treatment regimens for obese patients with chronic hepatitis C, it is important to use current knowledge of the metabolic effects of obesity," they wrote. "Thus, the most direct approach is to encourage weight loss and exercise before treatment."

They noted that people who are infected with HCV and who lose weight have been shown to have reductions in steatosis and significant decreases in fibrosis scores and activated stellate cells.

"Recently reported data suggest that treatment with the insulin-sensitizing medications metformin [Glucophage] and the thiazolidinediones (pioglitazone [Actos] and rosiglitazone [Avandia]) reduced serum alanine aminotransferase and histologic features of hepatic steatosis, inflammation, and fibrosis, as well as increased insulin sensitivity, in nondiabetic patients with nonalcoholic steatohepatitis; however, recent human data with metformin do not appear to be as promising," they noted.

Clinical trials will be needed to determine whether treating insulin resistance before or during antiviral therapy could be beneficial, the authors argued.

Other possible means for improving responses to combination therapy with pegylated interferons and Rebetol include longer duration of therapy "and, possibly, higher flat doses, which may counteract the decreased bioavailability of drug and increased resistance to interferon-based therapies," they added.