Digestive Diseases News
Spring/Summer 2009

Innate Immune Factors Associated with Race Influence Treatment for Chronic Hepatitis C

Early Response Predicts Final Outcome

A large percentage of people chronically infected with the hepatitis C virus (HCV) fail to control it with standard therapy.

A study funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has identified several factors, including African American race, that affect suppression of the virus during the first 28 days of treatment and predict final treatment outcome. Results suggest poor response to standard treatment may be due to differences in underlying genetic factors that influence innate immunity.

Hepatitis C is a bloodborne virus transmitted through the use of contaminated injection needles, during birth from an infected mother to her child, and through unprotected sex. Until reliable screening measures were put in place in 1992, hepatitis C was also spread through blood transfusions. Chronic hepatitis C affects about 3.2 million Americans and is the major cause of liver failure and liver cancer in the United States.

Doctors have known for some time that certain HCV strains, called genotypes, are more resistant to treatment, and that some patients, including African Americans and men, are more difficult to treat. The Study of Viral Resistance to Antiviral Therapy of Hepatitis C (Virahep-C) endeavored to understand why the success rate for standard hepatitis C treatment is lower among African Americans.

The Virahep-C cohort consisted of 401 men and women infected with genotype 1 HCV who identified themselves as being either “African American/black” or “Caucasian/white.” Volunteers were injected weekly with 180 micrograms of peginterferon (IFN) and orally took doses of 1,000 or 1,200 milligrams of ribavirin daily. People weighing more than 165 pounds took the higher dose of ribavirin. Treatment lasted at least 24 weeks.

Believing that assessing early viral kinetics—the rate at which virus is destroyed by treatment—would help identify factors related to immune response, Jay H. Hoofnagle, M.D., director of the NIDDK’s Liver Disease Research Branch, and colleagues analyzed Virahep-C data, focusing on changes in virus levels in patient blood during the first 28 days of standard treatment.

During this period, viral kinetics exhibited a biphasic pattern: levels of virus plummeted during the first 48 hours and then declined at a much slower rate during the weeks that followed. Viral levels, measured as the amount of viral RNA in the blood, were determined at baseline, 24 and 48 hours after the first peginterferon injection, and then before injections on days 7, 14, and 28. HCV RNA blood levels are an estimate of how much virus is in the body and an indicator for how well treatment is working.

Although treatment response varied widely among individuals, factors associated with a smaller reduction in viral RNA at day 28 included male sex, African American race, higher HCV RNA level at baseline, more severe hepatic fibrosis—a measure of liver damage—and higher body weight.

“In this prospective study, the early stages in HCV RNA levels during receipt of antiviral therapy for chronic HCV genotype 1 infection were highly predictive of the ultimate outcome,” wrote Jay H. Hoofnagle, M.D., and co-authors in their report, which appeared April 15, 2009, in The Journal of Infectious Diseases.

Lower Sustained Response

Even after adjusting for other factors, African Americans had a lower virological response than Caucasians at all five early time points. After 48 weeks of treatment, fewer African Americans—31 percent—had achieved a sustained virological response, meaning virus levels continued to stay low or undetectable, compared with Caucasians, at 55 percent.

Scientists were surprised that treatment success could be predicted so early. “The most striking finding of the study was that the ultimate antiviral efficacy of a 48-week course of IFN-based therapy for chronic HCV infection was, to a significant degree, determined by the viral kinetics only 24 to 48 hours after the first dose,” wrote Andrew W. Tai, M.D., Ph.D., and Raymond T. Chung, M.D., in a corresponding editorial commentary. Decreases in HCV RNA of African American patients were significantly lower by day 2 of treatment.

“The underlying cause of virological nonresponse and the reasons why it is more common among African American patients than among white patients were not clear,” according to Hoofnagle, et al., citing other Virahep-C studies that found the expression of interferon-stimulated genes to be blunted among people who didn’t respond well to therapy. The present findings suggest “these differences are fundamentally biologic.”

The report concludes that a future focus on virological, immunological, and genetic host factors will create new avenues toward more effective chronic hepatitis C therapies.

The National Digestive Diseases Information Clearinghouse, part of the NIDDK, offers free publications about hepatitis C. For more information, visit www.digestive.niddk.nih.gov.

[Top] [Next Article]

NIH Publication No. 09–4552
July 2009