Racial Difference in HCV Interferon Response emerges early

Racial Difference in HCV Interferon Response Emerges Early CME
News Author: Anthony J. Brown, MD
CME Author: Laurie Barclay, MD
Release Date: April 10, 2009;

Learning Objectives

Upon completion of this activity, participants will be able to:

Describe the association of overall 28-day decrease in HCV RNA levels with sustained virologic response in patients with HCV genotype 1 infection who were treated with peginterferon alfa-2a and ribavirin in Virahep-C.
Describe factors predicting a smaller decrease in HCV RNA level between baseline and day 28 in patients with HCV genotype 1 infection who were treated with peginterferon alfa-2a and ribavirin in Virahep-C.
Authors and Disclosures
Anthony J. Brown, MD
Disclosure: Anthony J. Brown, MD, has disclosed no relevant financial relationships.

Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Brande Nicole Martin
Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

April 10, 2009 — The results of a new study suggest that early differences in interferon-induced antiviral activity may explain why hepatitis C virus (HCV) therapy is usually less successful in blacks than in whites. This difference may be apparent within just one day of treatment initiation.

Findings from a number of studies have consistently shown that African Americans with chronic HCV infection have lower sustained virologic response rates than do Caucasian Americans, lead author Dr. Jay Hoofnagle, from the National Institutes of Health, Bethesda, Maryland, and colleagues state. To better understand this finding, the researchers analyzed data from 341 patients with chronic HCV, genotype 1 infection who were treated with peginterferon and ribavirin for at least 24 weeks. The main outcome measure was the treatment response rate within the first 28 days with a focus on the factors that influenced the response, such as HCV RNA levels and patient race, gender, and weight. The results are reported in The Journal of Infectious Diseases for April 15. The authors found that while HCV RNA levels dropped in almost all patients, the pattern and degree of decrease was different between African and Caucasian Americans. Although the researchers had expected a difference, the fact that it was apparent within just a day or two of therapy was a novel finding. The team also found that the early HCV RNA response was a reliable predictor of the sustained virologic response rate.

At 28 days, just 12% of African Americans were HCV RNA negative compared with 22% of Caucasian Americans, the report indicates. In addition to African American race, a higher initial HCV RNA level, more severe hepatic fibrosis, and higher body weight were predictive of a smaller reduction in HCV RNA levels through day 28. The new findings demonstrate "that the low rates of sustained virologic response among African American patients in response to interferon-based therapy appear to result, in large part, from impaired early viral kinetics," Drs. Andrew M. Tai and Raymond T. Chung, from Massachusetts General Hospital, Boston, write in a related editorial. "Further studies are necessary to uncover the relevant mechanisms that underlie this defect in interferon signaling or interferon-stimulated gene function, with the hope that such mechanisms can be manipulated to restore interferon responsiveness in the otherwise nonresponsive host," they add.

J Infect Dis 2009;199:1101-1103,1112-1120.

Reuters Health Information 2009. © 2009 Reuters Ltd.

Clinical Context

Combination therapy with peginterferon and ribavirin for 24 or 48 weeks is the current recommended therapy for chronic HCV infection, depending on the viral genotype. Sustained virologic response occurs in only 45% to 55% of patients with genotype 1 treated for 48 weeks with full doses of peginterferon and ribavirin. Viral and host factors both appear to affect the virologic response to combination therapy. Higher baseline levels of HCV RNA are associated with lower rates of sustained virologic response, and early viral kinetics are also predictive. Host factors previously shown to be linked to lower sustained virologic response include black race, male sex, higher body weight, older age, diabetes and insulin resistance, more advanced degrees of hepatic fibrosis, and the amount of peginterferon and ribavirin received.

Study Highlights

The Study of Viral Resistance to Antiviral Therapy of Hepatitis C (Virahep-C) prospectively looked at early changes in HCV RNA levels in a large cohort of black and white patients with chronic HCV infection caused by HCV genotype 1 and who were treated with peginterferon alfa-2a and ribavirin.
Analyses were restricted to 341 participants who completed the first 28 days of treatment without undergoing dose modification.
Average age of the participants was 51 years, 66% were men, 154 were black, and 187 were white.
Although virtually all patients had decreases in HCV RNA levels, the amount of the change varied dramatically.
The overall 28-day decrease in HCV RNA levels predicted a sustained virologic response at least as well as did the first- or second-phase viral kinetics responses.
Decreases in HCV RNA levels did not fit the published kinetics models for first- and second- phase viral responses.
Responders with the greatest 28-day decreases in the HCV RNA level had kinetics most similar to those from published models.
The likelihood of achieving a sustained virologic response by 28 days was 68% among patients with a decrease in the HCV RNA level of more than 2 log10 U/mL vs 22% among those in whom the decrease was less.
In patients with decrease in HCV RNA level of 4 log10 U/mL, chance of achieving a sustained virologic response by 28 days was 85%, which is similar to percentages among patients infected with genotype 2 or 3.
Characteristics predicting a smaller decrease in HCV RNA level between baseline and day 28 were black race, higher initial HCV RNA level, more severe hepatic fibrosis, and greater body weight.
Compared with white patients, black patients who had similar 28-day decreases in viral levels were still less likely to achieve a sustained virologic response.
For the entire Virahep-C cohort, the sustained virologic response rate was 13% higher among women vs men in both racial groups (24% in black men, 35% in black women, 47% in white men, and 61% in white women).
On the basis of these findings, the investigators concluded that racial differences in the response to antiviral therapy are caused by greater unresponsiveness to intracellular actions of interferon in blacks.
The investigators also suggest that standard doses of peginterferon and ribavirin may be suboptimal for patients with higher body weights.

Pearls for Practice
In the Virahep-C study of patients with HCV genotype 1 infection who were treated with peginterferon alfa-2a and ribavirin, the overall 28-day decrease in HCV RNA levels predicted a sustained virologic response at least as well as did the first- or second-phase viral kinetics responses.
Characteristics predicting a smaller decrease in HCV RNA level between baseline and day 28 were black race, higher initial HCV RNA level, more severe hepatic fibrosis, and greater body weight. Compared with white patients, black patients who had similar 28-day decreases in viral levels were still less likely to achieve a sustained virologic response