Hepatitis C virus infects 1.5 percent of the United States population but in African-Americans the rate approaches 5 percent. IFN has been the mainstay of therapy but the recent addition of Ribavirin has significantly improved therapeutic results with 40 percent of patients having sustained virologic clearance. However, in genotype 1 viral infection only 25 percent of patients develop sustained viral clearance. Recently, several virologic factors including genomic sequences in the NS5A and/or E2 region, have been identified as factors that promote greater resistance of genotype 1 virus to IFN. Host factors also influence response and recently, it has been demonstrated that African-Americans respond less well to IFN or IFN in combination with Ribavirin compared to Caucasians. Part of this failure may be due to the fact that greater than 90 percent of African- Americans with HCV are infected with genotype 1a or 1b virus compared to 70 percent of Caucasians. However, results suggest that response is also less in African-Americans compared to Caucasians infected with genotype 1 virus. The reason(s) for these differences in treatment response is not clear but could relate to differences in viral kinetics, IFN effectiveness, genomic sequences in the NS5A or E2 region, IFN pharmacokinetics, less immunologic response to viral infected hepatocytes or a combination of these factors. Recently, our group has detailed the kinetics of HCV. Results have shown that viral levels decrease with IFN in a biphasic manner, with the first phase accounting for a 0.5 to 2.0 log drop in RNA levels over 48 hours. This phase is explained by the effectiveness of IFN in inhibiting viral production. After this rapid drop, a second and slower phase of viral clearance ensues. This phase of RNA decline is highly variable between patients and is not dose dependent. It is theorized that this phase is dependent on immune-dependent elimination of HCV-infected liver cells. Patients having a fast reduction in viral levels clear virus early in therapy while patients who have slow or flat viral declines or viral rebound do not clear virus. We have re-examined the response of African- Americans and Caucasians infected with genotype 1 virus who have participated in our viral kinetic studies. Initial viral load, viral half-life and viral production were similar between races. However, no African-American patient (n=12) cleared virus in the first month of IFN while 9 of 29 Caucasians cleared virus. Viral log drop at one month was 2.0 logs less in African-Americans. Initial kinetic analysis suggests that this difference is in part secondary to a lesser degree of IFN effectiveness in inhibiting viral production in African-American. However, the second phaseof viral decline was gramatically less in African-Americans reflecting either lower immunologic response to HCV infected lever cells or selection of an IFN resistant viral strain. Thus, the Specific Aims are to further define early viral kinetic differences in African-Americans versus Caucasians with IFN monotherapy and combination therapy in order to gain theoretical insight into why African-Americans respond less well to therapy; to determine whether this lack of response can be explained by differences in IFN pharmacokinetics, intrinsic viral genomic factors that have been suggested to cause IFN resistance, and/or difference in immune recognition of HCV-infected liver cells.
