African American patients have a 2.0 fold greater rate of HCV infection than Caucasians and they are more likely to be infected with Genotype 1 virus which is inherently more resistant to IFN therapy. Recent studies indicate that sustained virologic response (SVR) with IFN therapy is less in African Americans than Caucasians although some of this reflects the greater rate of Genotype 1 infection. Nonetheless, the log drop in HCV RNA levels during IFN therapy is significantly less in African Americans. A recent study has shown that SVR is significantly improved in African American patients treated with IFN and Ribavirin and approached that seen in Genotype 1 infected Caucasians. Most preliminary results from other centers have not verified greatly improved SVR in African American patients. However, in most studies the percentage (5-10%) of African American patients enrolled was substantially less than Caucasians; and this occurred even though the population size of African American patients in the US and the number of patients infected would predict that African Americans should account for 20-25% of the HCV study population. This lower rate of study enrollment in the African American patients is not unique to HCV clinical trials and its cause is multi-factorial. However, the reported lack of response in African American patients is a growing detriment to enrollment especially since therapy is prolonged, expensive and fraught with side effects. Thus, means to predict non-SVR and SVR early in therapy would be very useful in treating patients who are unlikely to develop SVR. The lack of response of African American patients could result from differences in: compliance, body weight, gender, viral production and clearance rates, IFN effectiveness in blocking viral production, IFN pharmacokinetics, genomic differences in the virus and differences in humoral and cell mediated response. Some of these factors can be analyzed in the clinical studies while others will need to be addressed in the ancillary studies. The kinetics of HCV response to IFN has been recently described to undergo a biphasic response with the lsr phase being rapid, dose-dependent and accounting for a 0.5 to 2.0 log drop in RNA levels within 24 hours. This phase reflects the effectiveness of IFN in blocking viral production. A second slower phase of viral decline follows which is not IFN dose dependent, reflects the death of HCV infected liver cells and correlates with the serum half-life IFN. Its decline slope is an excellent predictor of SVR with IFN monotherapy or combination therapy. In preliminary results, we and others have shown that SVR may be even predicted as early as 24 hr of initiating IFN based on first phase kinetic parameters. Therefore, the first Specific Aim of this study is to assess using viral kinetic modeling principles the best and earliest predictor(s) of SVR. In preliminary studies, we have shown that African American patients treated with IFN alone have a blunted lsr phase viral decline but more importantly a significantly slower second phase viral decline. Based on preliminary findings that second phase decline correlates directly with IFN half-life and that SVR may be improved in African American patients treated with PEG-IFN, we would suggest that this multi-centered trial use PEG-IFN with Ribavirin in order to obtain optimum treatment results.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DK060349-01
Application #
6407041
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M1))
Program Officer
Robuck, Patricia R
Project Start
2001-09-15
Project End
2006-06-30
Budget Start
2001-09-15
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$178,818
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Jin, Runyan; Cai, Ling; Tan, Ming et al. (2012) Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1. Am J Gastroenterol 107:1675-83
Howell, Charles D; Gorden, Alexis; Ryan, Kathleen A et al. (2012) Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1. J Hepatol 56:557-63
Golden-Mason, Lucy; Bambha, Kiran M; Cheng, Linling et al. (2011) Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology 54:1559-69
Evon, Donna M; Esserman, Denise A; Ramcharran, Darmendra et al. (2011) Social support and clinical outcomes during antiviral therapy for chronic hepatitis C. J Psychosom Res 71:349-56
Conjeevaram, Hari S; Wahed, Abdus S; Afdhal, Nezam et al. (2011) Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology 140:469-77
Evon, Donna M; Ramcharran, Darmendra; Belle, Steven H et al. (2009) Prospective analysis of depression during peginterferon and ribavirin therapy of chronic hepatitis C: results of the Virahep-C study. Am J Gastroenterol 104:2949-58
Yee, L J; Im, K; Borg, B et al. (2009) Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection. Genes Immun 10:365-72
Hoofnagle, Jay H; Wahed, Abdus S; Brown Jr, Robert S et al. (2009) Early changes in hepatitis C virus (HCV) levels in response to peginterferon and ribavirin treatment in patients with chronic HCV genotype 1 infection. J Infect Dis 199:1112-20
Mengshol, J A; Golden-Mason, L; Castelblanco, N et al. (2009) Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes. Gut 58:964-73
Dove, Lorna M; Rosen, Raymond C; Ramcharran, Darmendra et al. (2009) Decline in male sexual desire, function, and satisfaction during and after antiviral therapy for chronic hepatitis C. Gastroenterology 137:873-84, 884.e1

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