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HCV Viral Load Decline at Day 2 of Interferon-based Therapy Predicts Sustained Response, Explains Poorer Outcomes in African-Americans

By Liz Highleyman

Declines in hepatitis C virus (HCV) viral load as early as 2 days after starting interferon-based therapy can help predict which individuals will achieve sustained virological response (SVR), and may help explain why different racial/ethnic groups respond differently to treatment, according to a study in the April 15, 2009 Journal of Infectious Diseases.

Past research has established that people of African descent do not respond as well as Caucasians to interferon-based therapy for hepatitis C; people of Asian descent tend to respond better than other groups, while data are mixed for Latino/Hispanic patients.

The Virahep-C trial, sponsored by the National Institutes of Health, was designed to look at factors associated with differences in hepatitis C treatment response, especially disparities between whites and African-Americans.

A total of 401 previously untreated genotype 1 chronic hepatitis C patients (205 Caucasian, 196 African-American) were treated with 180 mcg/week pegylated interferon alpha-2a (Pegasys) plus 1000-1200 mg daily weight-adjusted ribavirin, initially for 24 weeks. Those who did not achieve undetectable HCV RNA at this point stopped therapy, while responders continued treatment for a total of 48 weeks.

In the present analysis, Jay Hoofnagle from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and colleagues assessed early changes in HCV RNA levels among Virahep-C participants. The analysis was restricted to 341 patients who completed the first 28 days of therapy without dose modification (the point at which rapid virological response, or RVR, is assessed).

Results

HCV RNA levels decreased in almost all participants, but the amount of decline varied markedly from patient to patient.

Differences in HCV RNA decline between whites and African-Americans reached statistical significance by day 2 of treatment.

At day 28, 22% of Caucasians had undetectable HCV RNA compared with 12% of African-Americans.

The overall decrease in HCV RNA at day 28 predicted SVR at least as well as first-phase or second-phase viral kinetics.

Factors associated with a smaller decline in HCV RNA from baseline to day 28 included:

African-American race;
Higher initial HCV RNA level;
More severe hepatic fibrosis;
Higher body weight.

African American patients whose 28 day decline in viral load was similar to that of white patients were still less likely to achieve SVR.

These findings led the researchers to suggest that racial differences in response to standard anti-HCV therapy are likely related to biological -- likely genetic -- differences in how the body responds to interferon.

"The underlying cause of virological non-response and the reasons why it is more common among African Americans than Caucasian Americans are not clear," the study authors wrote. "[T]he current analyses demonstrated that these differences are fundamentally biologic and become apparent within 24 to 48 hours of starting therapy."

In conclusion, they wrote, "These results suggest that racial differences in the response to antiviral therapy are due to greater unresponsiveness to intracellular actions of interferon in African American individuals and that standard doses of peginterferon and ribavirin may be suboptimal for patients with higher body weights."

Previously presented Virahep-C research has looked at associations between racial differences in treatment response and interferon pharmacokinetics, genetic differences in interferon signaling, and major histocompatibility genes.

In an editorial accompanying Hoofnagle's report, Andrew Tai and Raymond Chung from Massachusetts General Hospital wrote that this analysis "demonstrates that the low rates of SVR in African American patients in response to interferon-based therapy appear to result, in large part, from impaired early viral kinetics. Further studies are necessary to uncover the relevant mechanisms that underlie this defect in interferon signaling with the hope that such mechanisms can be manipulated to restore interferon responsiveness in the otherwise nonresponsive host."

If poorer outcomes among African-Americans are shown to be due to reduced responsiveness to interferon, differences in treatment response might diminish with the use of investigational antiviral agents that directly target various stages of the HCV life cycle rather than modulating immune function.

Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Division of Hepatology, University of Maryland School of Medicine, Baltimore, MD; Departments of 3Biostatistics and Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; Division of Gastroenterology and Hepatology, New York-Presbyterian Medical Center, New York, NY.

6/02/09

References

JH Hoofnagle, AS Wahed, RS Brown, and others. Early Changes in Hepatitis C Virus (HCV) Levels in Response to Peginterferon and Ribavirin Treatment in Patients with Chronic HCV Genotype 1 Infection. Journal of Infectious Diseases 199(8):1112-1120. April 15, 2009

AW Tai and RT Chung. Racial Differences in Response to Interferon?Based Antiviral Therapy for Hepatitis C Virus Infection: A Hardwiring Issue? Journal of Infectious Diseases 199(8): 1101-1103. April 15, 2009.