Virahep-C Clarifies Reasons for Lower Response Rates Among African Americans

By Liz Highleyman

Past research has established that African Americans do not respond as well as Caucasians to interferon-based hepatitis C treatment. In past studies, typical sustained virological response (SVR) rates to combination therapy with pegylated interferon plus ribavirin have been around 25%-30% for African Americans compared with around 50%-55% for Caucasians, among patients with genotype 1 HCV.

Virahep-C is a trial sponsored by the National Institutes of Health to look at differences in hepatitis C treatment response; unlike most previous studies, it enrolled roughly equal numbers of African Americans and Caucasians.

The study included 401 treatment-naïve patients (196 African Americans and 205 Caucasians) with genotype 1 HCV who were treated with 180 mcg/week pegylated interferon alpha-2a (Pegasys) plus 1000-1200 mg daily ribavirin, initially for 24 weeks. Those who did not achieve virological response (undetectable HCV RNA) at this point stopped therapy, while responders continued treatment for a total of 48 weeks.

Several analyses presented at the recent Digestive Disease Week conference in Los Angeles looked at some of the possible reasons for the observed racial variation in treatment response.

Pegylated Interferon Pharmacokinetics and Pharmacodynamics

In one analysis, C. Howell and colleagues looked at the early pharmacokinetics and pharmacodynamics of pegylated interferon and their relation to virological response. This analysis included data from 96 patients who did not have their pegylated interferon doses adjusted during the first four weeks of therapy. Serum levels of pegylated interferon and 2,5-OAS (an enzyme induced by interferon) were measured before treatment and on days 1, 2, 3, 7, 14, and 28.

African American and Caucasian subjects were similar with regard to age, gender distribution, body weight, body mass index (BMI), alcohol and tobacco use, liver histology, creatinine clearance, HCV viral load, and HCV genotype 1 subtype distribution; however, the African Americans had a lower mean serum ALT level.

Results

After four weeks of therapy with pegylated interferon plus ribavirin, a lower rapid virological response rate was observed among the African American patients. There were no differences between African American and Caucasian patients in either the pegylated interferon maximum concentration (Cmax) or area under the curve (AUC) from day 0 to 7 after the first dose. African Americans were more likely to achieve maximum concentration (time to maximum, or Tmax) by day 3 (P = 0.03). African Americans had a significantly greater pegylated interferon level on day 28 (18.0 vs 15.5 ng/mL; P = 0.03) and higher 2,5-OAS levels on days 2, 3, 14, and 28 (P < 0.05). However, African Americans had a significantly smaller decline in serum HCV RNA from baseline through day 28 (P = 0.02). A negative correlation between serum pegylated interferon level and HCV RNA levels on days 7, 14, and 28 was observed in Caucasians, but not in African Americans. There was also a negative correlation between serum 2,5-OAS levels on days 2 through 14 and HCV RNA levels from days 2 through 28 in Caucasians but not in African Americans.

Conclusion

The authors concluded that the weaker virological response among African American patients with genotype 1 compared with Caucasians during the first four weeks of treatment with pegylated interferon plus ribavirin was not explained by racial differences in serum pegylated interferon or 2,5-OAS kinetics.

Genetic Differences in Interferon Signaling

In another analysis, X. Su and colleagues looked at genetic differences in response to interferon signaling. During interferon-based therapy, interferon signaling events in host cells are triggered by binding of interferon alpha and beta to their respective receptors. This leads to the activation of interferon signaling pathways, transcription of interferon-stimulated genes, and induction of an antiviral response.

The researchers analyzed polymorphisms (variations) in five genes involved in the interferon signaling pathway (STAT1, STAT2, IFNaR1, IFNaR2, and IRF9) and 12 interferon-stimulated genes (MX1, MX2, OAS1, OAS2, OAS3, OASL, IRF7, G1P2, G1P3, IFI35, PKR, and IP10) in 373 individuals (180 African Americans and 193 Caucasians) who consented to genetic analysis. They selected 91 different single nucleotide polymorphisms (SNPs) on the basis of location, minor allele frequency, and potential function; those that were significantly associated with SVR were further analyzed in a regression model that included race, sex, baseline HCV viral load, Ishak fibrosis score, and pegylated interferon dose.

Results

A consistent association with SVR was observed in both racial groups for SNP rs3213545 in the OASL gene ("T" allele frequency 50.5% in Caucasians, 30.6% in African Americans) The overall SVR rate was 50.7% among "T" allele carriers compared with 34.1% among non-"T" carriers, a statistically significant difference. When adjusted for other variables including race, the association between this SNP and SVR remained significant (P = 0.026). SNPs in the STAT1 and STAT2 genes were significantly associated with SVR in one race, but not in the combined analysis adjusting for race.

Conclusion

The researchers concluded that SNP rs3213545 in the OASL gene was associated with sustained response in chronic hepatitis C patients. Although the function of this SNP is not known, the study demonstrated that this interferon-induced pathway "is critical for the host-mediated antiviral effect in response to interferon-based based therapy." This was further supported by differences in the expression of OASL messenger RNA (mRNA) between patients who achieved early virological response and those who did not.

Role of Major Histocompatibility Complex

The major histocompatibility complex (MHC) is a group of genes involved in immune response, including distinguishing "self" from "non-self" antigens of foreign microorganisms. A subset of human leukocyte antigen (HLA) genes encode antigen-presenting proteins on cell surfaces. MHC activity is thought to play a role in response to HCV, and some MHC alleles (variations) appear to be associated with self-limited infection, or spontaneous viral clearance. MHC may also influence response to interferon-based therapy.

An analysis by S. Rhodes and colleagues aimed to assess the association between HLA alleles and sustained response to pegylated interferon plus ribavirin. This analysis included data from the same 373 patients as the previous study. Genotyping of Class I and Class II HLA genes was performed, and alleles with a frequency of 5% or greater in one racial group and a significantly different racial distribution were selected for inclusion in a regression model that adjusted for race, age, gender, baseline viral load, Ishak score, and interferon dose.

Results

When analyzed simultaneously in a multivariate regression model, all three alleles were independently associated with SVR, as shown in the table. An association between the A*02 allele and SVR was observed in a univariate analysis of Caucasian patients (P = 0.005) and in a race-adjusted analysis (P = 0.003). Alleles B*58 and DPB*1701 were associated with SVR in a univariate analysis of African Americans (P = 0.007 and 0.02, respectively), and in a race-adjusted analysis (P = 0.003 and 0.008, respectively).

Conclusion

The authors concluded that the HLA alleles A*02, B*58, and DPB*1701 are independently associated with sustained response to pegylated interferon plus ribavirin. However, they noted, these alleles could not explain the observed racial difference in SVR. The HLA A*02 allele has previously been reported to be associated with self-limited HCV infection in studies of Caucasian patients. The associations involving the B*58 and DPB*1701 alleles have not been reported in previous studies, likely because African Americans have been underrepresented in prior research.

HCV-Specific Immune Responses

Finally, a study by J.R. Burton and colleagues aimed to assess whether pretreatment HCV-specific immune responses are related to race, and whether these are associated with virological response to therapy with pegylated interferon plus ribavirin.

Individuals who experience spontaneous hepatitis C clearance have vigorous HCV-specific cellular immune responses. Studies have shown that African Americans have a lower rate of spontaneous clearance compared with Caucasians, just as they have poorer response to interferon-based therapy.

In this analysis, CD4 T-cell responses of 353 patients (179 African Americans and 174 Caucasians) were quantified at baseline using a sensitive ELISpot (enzyme linked immunospot) assay. The researchers measured the response of peripheral blood mononuclear cells (PBMCs) to HCV core, E2, NS3, NS4, and NS5 antigens, as well as negative and positive control antigens.

Results

A combined baseline HCV antigen response of at least 168 interferon-gamma ELISpots per 106 PBMCs was significantly associated with SVR. Overall, 43.2% of patients at or above this threshold experienced SVR, compared with 28.2% of patients with poorer response to HCV antigens (P = 0.007). Among Caucasians, 53.3% of patients with responses at or above this threshold experienced SVR, compared with 38.5% with lesser responses. Among African Americans, the corresponding values were 30.6% and 22.5%. A multivariable regression analysis confirmed the independent association between baseline interferon-gamma ELISpot response and SVR (P = 0.04).

Conclusion

The researchers concluded that baseline HCV-specific immunity is associated with sustained virological response in patients undergoing antiviral therapy, regardless of race.

6/13/06

References

C. Howell, T. Dowling, M. Haritos, and others. Relationship between serum peginterferon and 2,5-OAS kinetics and virologic responses in African Americans and Caucasians patients with chronic hepatitis C, genotype 1, during peginterferon combination therapy. Abstract 199. Digestive Disease Week 2006 (DDW 2006). May 20-25, 2006. Los Angeles, CA.

JR Burton, J Klarquist, K Im, and others. Stronger baseline HCV-specific immunity is associated with a higher likelihood of a sustained virological response to combination antiviral therapy of chronic hepatitis C. Abstract S1057. DDW 2006. May 20-25, 2006. Los Angeles, CA.

X Su, S Rhodes, L Yee, and others. Association of interferon signaling pathway and interferon stimulated genes with response to pegylated interferon and ribavirin therapy in HCV infected Caucasian and African American patients. Abstract 2. DDW 2006. May 20-25, 2006. Los Angeles, CA.

S Rhodes, H Erlich, K Im, and others. Association between HLA allele A*02, B*58, DPB*1701 and sustained virologic response to pegylated interferon and ribavirin therapy in chronic HCV genotype 1-infected, treatment-naïve Caucasian and African Americans. Abstract 656. DDW 2006. May 20-25, 2006. Los Angeles, CA.