There are several reasons why some people may fail to achieve a sustained response to treatment for hepatitis C. Now, a new study suggests that insulin resistance can be added to the list.¹

"We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin," wrote Manuel Romero-Gomez, MD, in the Hepatology Unit at Hospital Universitario de Valme in Sevilla, Spain, and his fellow physicians.

While it's been well known for several years that people with the genotype 1 strain of the hepatitis C virus and/or those with a higher viral load have lower odds of achieving a sustained response to therapy, "the impact of host factors in the chance of curing hepatitis C is not well known," Romero-Gomez explained, in an e-mail interview with Priority Healthcare.

Questions Surrounding Impact of Insulin Resistance
Sustained virologic response, or SVR, is the absence of detectable levels of the hepatitis virus in a patient for a minimum of 6 months after treatment has ended.² There are various reasons why some patients may achieve an SVR after treatment, while others may not. According to recent medical research, older patients, heavier patients, those infected with the most common strain of hepatitis C known as genotype 1, those with higher viral loads, patients diagnosed with liver cirrhosis, African-American or Hispanic patients, and men are less likely to achieve an SVR after pegylated interferon therapy combined with the oral antiviral medication, ribavirin.³

Insulin resistance is a condition in which there is too much insulin in your blood. This happens because your cells, which normally take up insulin to help them convert sugars from food into energy, instead block it. But your pancreas continues making insulin anyway, increasing levels of the hormone. In the end, your body doesn't use sugar properly. Insulin resistance is often seen in diseases or conditions like diabetes, high cholesterol, and hypertension.⁴

In previous research, Romero-Gomez and his team found insulin resistance and factors associated with the leptin system in the body played key roles in steatosis (the medical term for fatty liver) and the progression of fibrosis. "Also, we observed a strong relationship between several factors as weight, increased body mass index, steatosis, insulin resistance, and hyperleptinemia, and some of them had been associated with [treatment] response," Romero-Gomez explained. (Hyperleptinemia is a condition in which abnormally high levels of leptin are found in the blood. Leptin is a hormone produced by fat cells that plays a part in weight regulation).

Examining the Role of Insulin Resistance
To determine whether insulin resistance lowers the odds of achieving an SVR to hepatitis C therapy, Romero-Gomez and his team recruited nearly 160 men for their analysis. The patients, on average, were about 41 years of age, had been diagnosed with chronic hepatitis C, and were given interferon plus ribavirin treatment.

During the study, each patient underwent a range of tests that included measurements of leptin and insulin in the blood. The researchers also determined whether each man was insulin resistant and calculated each patient's body mass index. Body mass index (BMI) is a clinical measurement of weight relative to a person's height.

When the research was completed, Romero-Gomez and his colleagues determined that younger age, a lower BMI, lower blood levels of leptin, and a lack of insulin resistance increased the likelihood that a patient would achieve an SVR to therapy. In contrast, higher liver fibrosis levels tended to reduce a patient's odds of responding to treatment.

"There was no association with viral load, sex, type of interferon, or cholesterol levels," they wrote. "A sustained virological response was achieved in 43.4% of genotype 1 and 89% of genotype 2 and 3 patients," they wrote. Liver inflammation and steatosis also had no effect on a particular patient's SVR. Each of findings was considered significant, meaning that they did not likely come about by chance alone.

The investigators concluded that those with genotype 1 were about 3.5 times less likely to achieve an SVR, and those who were insulin resistant were about two times less likely.

A combination of the two was even more detrimental. In those with both genotype 1 and insulin resistance, an SVR was achieved in only about one-third of the men who took part in the study compared to more than 60 percent of those with the genotype 1 strain and no insulin resistance. Those with both insulin resistance and the genotype 1 strain had three times the risk of failing therapy, Romero-Gomez's group concluded.

"Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin," the research team wrote.

Underlying Theories
Romero-Gomez points to some theories behind the influence of insulin resistance on SVR. In previous studies of hepatitis C in culture, it was shown that high levels of insulin (a condition known as hyperinsulinemia) helped block production of natural interferon, an antiviral protein in the body on which synthetic interferon treatment is based. "In this model, interferon alone blocked greater than 90% of the replication of the virus," Romero-Gomez explained. "However, when interferon was added together with insulin (at greater doses), replication was maintained and interferon was found ineffective."

He says insulin resistance could be a key feature of patients who fail to respond to therapy, such as those with the genotype 1 strain, and could thus block interferon production. In this context, "treating hyperinsulinemia could be very intriguing," Romero-Gomez said.

He and his colleagues are currently designing a clinical trial to test the efficacy of interferon/ribavirin combination treatment along with metformin (Glucophage, Glucophage XR, Bristol-Myers Squibb) currently approved as a diabetes therapy to determine if treating insulin resistance could improve a person's odds of achieving an SVR to HCV therapy.

1. Romero-Gomez M, Del Mar Violoria M, Andrade RJ et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005 Mar;128(3):636-41.
2. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002 Sep 26;347(13):975-82.
3. Hepatitis Neighborhood. Responding to Hepatitis Medications (or not). Available at: http://www.hepatitisneighborhood.com/content
/understanding_hepatitis/treating_hepatitisc_138.aspx. Accessed April 12, 2005.
4. American Academy of Family Physicians. Insulin Resistance Syndrome. Available at: http://familydoctor.org/660.xml. Accessed April 20, 2005.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.