 |
|
|
| |
African-Americans' response to Interferon: preliminary results from Virahep C Study
|
| |
| |
Reported by Jules Levin
DDW May 23, 2006, Los Angeles
Results from the study designed to understand why African-Americans have less response to interferon ViraHep C are starting to come in. At DDW several initial results were reported and discussed. So far the preliminary data suggests what was previously thought, genetic differences, but a better understanding of this may be developing.
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
C. Howell1; T. Dowling1; M. Haritos2; N. Terrault3; W. Thelma5; M. Taylor6
1. Medicine, University of Maryland Baltimore, Baltimore, MD, USA.
2. University of Pittsburg, Pittsburg, PA, USA.
3. University of California , San Francisco, PA, USA.
4. University of Miami, Miami, FL, USA.
5. Rush University , Chicago, IL, USA.
6. Indiana University, Bloomington, IN, USA.
Note from Jules Levin; my impression from Dr Howell's talk was that genetic differences or polymorphism between African-Americans and Caucasians may be responsible for different responses to interferon stimulating therapy.
African Americans (AA) infected with hepatitis C virus (HCV) genotype 1 have significantly lower rates of HCV clearance than Caucasian Americans (CA) following treatment with peginterferon alfa (PEGIFN) and ribavirin. In the Virahep-C study, this racial difference in virologic response was observed during the first 4 weeks of therapy.
Aim: To compare PEGIFN pharmacokinetics and pharmacodynamics (i.e. serum 2,5 OAS kinetics) in relationship to virologic responses during the first 28 days of PEGIFN-2a and ribavirin treatment in AA and CA HCV genotype 1 patients. Methods: 401 treatment-naive, HCV genotype 1 patients (196 AA and 205 CA) were treated with PEGIFN-2a (180 mcg/wk) and ribavirin (1000-1200 mg/day) for up to 48 weeks. Ninety-six patients who received PEGIFN without dose alteration during the first 4 weeks of treatment and who had PEGIFN and 2,5-OAS serum levels measured before treatment and on treatment-days 1, 2, 3, 7, 14 and 28 were selected for this study. PEGIFN and serum 2,5-OAS (pharmacodynamic marker) levels were measured by ELISA and by RIA (Roche Molecular Diagnostics, Alameda, CA). The maximum PEGIFN concentration (Cmax) and area under the serum concentration-time curve (AUC) values from day 0 to 7 were determined using non-compartment PK analysis. Serum HCV RNA levels were measured using the Amplicor HCV Monitor Test, version 2.0 assay.
Results: At baseline, AA and CA patients were similar in regards to age, gender distribution, body weight, BMI, alcohol or tobacco use, liver histology, creatinine clearance, baseline HCV RNA levels, and HCV 1 subtype distribution, but AA had a lower mean serum ALT level (p = 0.003). There were no differences between AA and CA in either Cmax or AUC from day 0-7 after first PEGIFN dose, but AA were more likely to have a Tmax by day 3 (p = 0.03) and had a greater PEGIFN level on day 28 (18.0 ± 8 vs. 15.5 ± 7 ng/mL, p = 0.03) and higher 2,5-OAS levels on day 2, 3, 14, and 28 (p < 0.05). In contrast, AA had a significantly smaller decline in serum HCV RNA from pretreatment to day 28 (p =0.02 day 14 and 28). There was a negative correlation between serum PEGIFN-2a (p < 0.05) and HCV RNA levels on days 7 (r = -0.23, p = 0.09), 14 (r = -0.30, p = 0.03), and 28 (r = -0.32, p = 0.02) in CA but not in AA. Likewise, there was a negative correlation between serum 2,5-OAS levels on day 2-14, and HCV RNA levels from day 2-28 in CA (p < 0.05) but not in AA.
Conclusion: The weaker virologic response in AA HCV genotype 1 patients compared to CA patients during the first 4 weeks of PEGIFN-2a and ribavirin treatment is not explained by racial differences in serum PEGIFN and serum 2,5-OAS kinetics.
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 naive Caucasian and African Americans
S. Rhodes1; H. Erlich2; K. Im3; J. Wang2; J. Li2; T. Bugawan2; L. Jeffers4; X. Tong1; X. Su1; L. J. Lee3; T. Liang5; H. Yang1
1. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
2. Roche Molecular Systems, Alameda, CA, USA.
3. University of Pittsburgh, Pittsburgh, PA, USA.
4. University of Miami, Miami, FL, USA.
5. National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, USA.
Background: Responses to interferon therapy for hepatitis C virus (HCV) infection differ between Caucasian (CA) and African Americans (AA) which implies a role for host genetic factors. Major histocompatibility complex (MHC) activity is thought to be associated with response to HCV and some MHC alleles appear associated with self-limited infections. The role of MHC in host response to therapy is less clear, possibly due to small sample sizes in many studies. To date there have been no reports on MHC genes and response to therapy in AA.
Aim:Our aim is to evaluate the relationship between HLA alleles and sustained virologic response (SVR) to pegylated interferon plus ribavirin (PEG+Rb) in a large cohort of CA and AA HCV patients.
Methods:The Virahep-C study treated 401 HCV infected patients with PEG+Rb for 24 weeks. Participants HCV-RNA negative at week 24 continued on therapy for another 24 weeks and were followed to determine SVR (PCR negative for HCV-RNA at week 72). Genotyping of Class I and II HLA genes was performed by Roche HLA linear array typing system on 373 participants who consented to host genetics studies (194/205 CA, 179/196 AA). Alleles with a frequency of 5% or greater in one racial group and a p-value <0.05 in race-adjusted carrier analysis were selected for inclusion in regression modeling. A modified Poisson regression model adjusting for age, gender, race, baseline viral load, Ishak score, dose received and other alleles provided relative risks.
Results:An association between the A*02 allele and SVR was found in univariate analysis of CA (p=0.005) and in race-adjusted analysis (p=0.003). B*58 and DPB*1701 were associated with SVR in univariate analysis of AA (p=0.007, p=0.02, respectively) and in race-adjusted analysis (p=0.003, p=0.008, respectively). All three alleles, when fitted simultaneously in multivariable regression model, were independently associated with SVR (Table).
Conclusions: The A*02, B*58 and DPB*1701 alleles are independently associated with SVR to PEG+Rb therapy. However, these HLA alleles could not explain the observed racial difference in SVR. The HLA A*02 allele was previously reported to be associated with self-limited infection in CA population. The B*58 and DPB*1701 associations, not previously reported, are mainly driven by AA population which were underrepresented in early studies. Further confirmation of these associations in independent samples is warranted
A comprehensive genetic approach defines the importance of a functional single nucleotide polymorphism of the interferon-gamma gene in interferon-alpha-induced and spontaneous recovery from hepatitis C
B. B. Borg1; Y. Huang1; H. Yang2; X. Su2; S. Rhodes2; X. Tong2; G. Tang2; R. Sapp1; C. D. Howell3; H. R. Rosen4; C. L. Thio5; D. L. Thomas5; T. Liang1
1. Liver Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD, USA.
2. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
3. University of Maryland School of Medicine, Baltimore, MD, USA.
4. Division of Gastroenterology/Hepatology and Liver Transplantation Program, Oregon Health and Sciences University, Portland, OR, USA.
5. Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Background/Aims: Interferon (IFN)-gamma is an important cytokine that has direct antiviral effect and regulates cellular immune responses to a variety of intracellular pathogens including hepatitis C virus (HCV). Polymorphisms of cytokine genes have been associated with disease outcome and treatment response in hepatitis C. In this study, we performed a comprehensive analysis of IFN-gamma gene polymorphisms in HCV-infected patients for association with response to IFN-alpha-based therapy.
Methods: We genotyped 10 single nucleotide polymorphisms covering the entire IFN-gamma gene in two cohorts. The first was a cohort of 292 HCV-infected patients (25% African American (AA) and 75% Caucasian American (CA)) who had received IFN-based therapy. The second was a well-characterized cohort of intravenous drug users (90% AA, n=251) who had either spontaneously cleared HCV infection or became chronically infected with HCV (Khakoo et al, Science 2004;305:872-4). Cochran Mantel Hanzel (CMH) statistics was used to assess the association between IFN-gamma gene polymorphisms and treatment response.
Results: A single nucleotide polymorphism (SNP) located in the proximal promoter region at position -764G was significantly associated with sustained virological response (SVR) [p=0.03, ORcmh=2.22 (1.09-4.53)]. This correlation was also observed in a more restricted analysis comparing all SVRs with only the non-responders who received the optimal standard therapy (PegIFN+ribarivin) [p=0.02, ORcmh=2.98 (1.17-7.59)]. This allele was significantly more common in CA than in AA (8.26% vs 2.70%, p=0.02). In the second cohort, this SNP was significantly associated with spontaneous recovery from HCV infection [p=0.04, OR=3.51(0.98-12.49)]. Functional analysis with reporter gene assay showed that T cell line transfected with the variant -764G IFN-gamma promoter, which is associated with treatment response and spontaneous recovery, had a 2-3 fold higher luciferase activity than the common -764C construct. This observation supports the functional importance of this polymorphism in the interferon-gamma gene.
Conclusion: Our findings suggest that the SNP at position -764 of IFN-gamma promoter is functionally important in determining viral clearance and treatment response and may be used as a genetic marker to predict the response of IFN-based therapies in HCV-infected patients.
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
X. Su1; S. Rhodes1; L. Yee2; K. Im2; X. Tong1; C. Howell3; M. Haritos2; T. Liang4; M. Taylor5; H. Yang1
1. Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
2. Coordinating Center, University of Pittsburgh , Pittsburgh, PA, USA.
3. Hepatology Research, University of Maryland, Baltimore, MD, USA.
4. Liver Diseases Section, NIDDK, Bethesda, MD, USA.
5. Microbiology and Molecular Biology, Indiana University, Bloomington, IN, USA.
Background and aims: Only 52% of Caucasian(CA)and 28% of African Americans(AA)infected with HCV genotype 1 achieved a sustained virologic response(SVR) following treatment with pegylated interferon(IFN) + ribavirin. This difference in SVR both between and within racial groups suggested that host genetic factors may play an important role in host response to IFN-based therapy. During IFN-based therapy, IFN signaling events in the host cells are triggered by binding of IFNa/B to their receptors. This leads to the activation of IFN signaling pathways, transcription of IFN stimulated genes(ISGs) and induction of the anti-viral response. We performed a candidate gene study to evaluate the association of SVR with genetic polymorphisms of 5 IFN signaling pathway genes(STAT1, STAT2, IFNaR1, IFNaR2 and IRF9) and 12 ISGs (MX1, MX2, OAS1, OAS2, OAS3, OASL, IRF7, G1P2, G1P3, IFI35, PKR and IP10) in patients with chronic HCV.
Methods: In the Virahep-C study, 401 treatment-naive, HCV genotype 1 patients were treated with pegylated-IFN-alfa2a and ribavirin for 48 weeks. Of these, 373 (180 AA and 193 CA) consented for the host genetics study and were genotyped for 91 SNPs from these genes using Illumina BeadArrayTM technology. These SNPs were selected based on location, minor allele frequency and potential function. SNPs with a significant association (p<0.05) with SVR, controlling for race, were further analyzed in a regression model that included other SVR associated factors: sex, race, pre-treatment viral load, Ishak fibrosis score and dose received.
Results: A consistent association was observed in both racial groups for SNP rs3213545 in the OASL gene (T allele frequency: 50.5% in CA, 30.6% in AA. Among T carriers SVR was 50.7% whereas only 34.1% among non-T-carriers). Bivariable analysis adjusted only for race, this association was significant (RR=1.27, p=0.026). When adjusted for other covariates including race, the significant association between this SNP and SVR remained at a=0.05 level (RR=1.3, 95%CI=1.03-1.6, p=0.026). SNPs in STAT1 and STAT2 genes were significantly associated with SVR in one race, but not in the combined analysis adjusting for race.
Conclusion: A synonymous SNP in OASL gene is associated with SVR in chronic HCV patients. Although the function of this SNP is not obvious, the present study identifies this IFN induced pathway as critical for the host mediated antiviral effect in response to IFN based therapy. This result is further supported by observed differences in the expression of OASL mRNA between patients who had an early response and those who had a static response to therapy in the same Virahep-C cohort.
IL-6, TNF-a and CRP gene polymorphisms are associated with increased colon cancer risk in African Americans compared to Whites in the North Carolina Colon Cancer Study
T. O. Keku1; J. Galanko1; S. Omofoye1; R. Holston1; J. Peacock1; J. Barnes1; C. Martin1; R. S. Sandler1
1. Center for Gastrointestinal Biology & Disease, University of North Carolina, Chapel Hill, NC, USA.
Background: Among major US ethnic groups, African Americans have the highest incidence and mortality of colon cancer. However, critical questions remain unanswered about genetic susceptibility to colon cancer in African Americans. Cytokines mediate immune and inflammatory responses, which may act in neoplastic pathways. Genetic variants that influence cytokines levels may thus affect colon cancer risk.
Aim: To evaluate IL-6 (G -174 C), TNF-a (G -308 A), CRP (G -1081 A) genetic polymorphisms among African Americans and Caucasian Whites in relation to the risk of colon cancer and assess interactions with lifestyle-dietary factors.
Methods: We analyzed 528 incident colon cancer cases (231 African Americans, 297 Whites) and 836 controls (306 African Americans, 530 Whites) from a large population-based case control study in North Carolina. Controls were frequency matched to cases on age, race and sex. Consenting subjects provided blood specimens, information about lifestyle and diet histories, and anthropometric measurements. IL-6, TNF-a, CRP genotypes were determined by the TaqMan assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (CI) for variant genotypes while controlling for potential confounders such as age, sex, non-steroidal anti inflammatory drugs (NSAIDs), and body mass index (BMI).
Results: IL-6 and TNF-a variant genotypes were significantly associated with increased risk of colon cancer among African Americans, compared to wildtype genotypes (IL-6 GC+CC, OR 1.7, 95% CI 1.0-2.8; TNF-a GA+AA, OR 1.6, 95% CI 1.0-2.4), but not in Whites. However, the CRP GA+AA variant genotype showed a modest association with colon cancer in Whites compared to wildtype (OR 1.3, 95% CI 1.0-1.8). Interestingly, in a combined analysis with all three genes, using common wildtypes as referent, having one or more variants was significantly related to colon cancer risk in both African Americans and Whites (OR 1.3, 95% CI 1.0-1.6) but this association was stronger for African Americans (OR 1.4, 95% CI 0.9-2.0; Whites OR 1.2, 95% CI 0.9-1.7). No interactions were observed with BMI and NSAIDs use. However, the risk of variant genotypes was greater among persons with elevated waist-to-hip ratios (WHRs). The OR for having greater-than-median WHR plus 1 or more variants was 2.2 (95% CI 1.6-3.2), compared to persons below median WHR having no variants.
Conclusion: These results suggest that genetic polymorphisms in IL-6, TNF and CRP strongly contribute to colon cancer susceptibility, particularly in African Americans.
Spontaneous Clearance of Hepatitis C Virus Infection in African American Patients
X. Zhao1; M. Ramaswamy1; M. Tang3; M. Black2; X. Ma1
1. Department of Medicine, Graduate Hospital, Philadelphia, PA, USA.
2. Department of Medicine, Temple University Hospital, Philadelphia, PA, USA.
3. Radnor High School, Radnor, PA, USA.
Background/Aim: Spontaneous clearance of hepatitis C virus (HCV) infection is the outcome of the interplay between host immunity and virus behavior. HCV has been shown to have different viral kinetics in African Americans (AA) as opposed to Caucasians. We look at the spontaneous clearance rate in these two groups and the association of viral clearance with race, environmental factors, and other viral coinfection.
Method: Retrospective chart review was performed on 293 patients with positive HCV Ab who were followed at our liver clinic from 2002 to 2005. Patients with spontaneous clearance were identified as having positive HCV Ab confirmed by RIBA and undetectable viremia without prior treatment; chronically infected patients were identified as either having active viremia or negative viremia after treatment. Patients with diagnosed autoimmune diseases were excluded. Data were collected on patient demographics, risk factors, and clinical characteristics. Statistical analysis was performed using univariate and multivariate logistic regression analyses.
Result: There were 191 AA, 74 Caucasians, 19 Asians, and 9 Latin-Americans in our study. The spontaneous clearance rate in AA and Caucasian patients was 9.4% (18/191) and 20.3% (15/74) respectively (P=0.021). No difference was observed in age, gender, and weight between the two groups. In univariate analysis, HBsAg positivity had a positive association with viral clearance (odds ratio [OR] 6.08; 95% CI 1.56-23.80; P=0.016); black race (OR 0.45; 95% CI, 0.22-0.91; P=0.027) and alcohol abuse (OR 0.23; 95% CI, 0.09-0.58; P=0.001) were associated with decreased HCV clearance; age, gender, and risk factors (IVDA, blood transfusion) did not show significant association with viral clearance. In multivariate analysis adjusting for gender, race, alcohol, and HBV coinfection, HBsAg remained positively associated with viral clearance (OR 14.15; 95% CI 2.74-72.97; P=0.001), while black race (OR 0.42; 95% CI 0.19-0.93; P=0.032) and alcohol abuse (OR 0.18; 95% CI 0.06-0.52; P=0.001) were still negatively associated with viral clearance.
Conclusion: Spontaneous clearance of HCV is lower in African Americans than in Caucasians; HBV coinfection is associated with increased likelihood of HCV clearance. The primary viral clearance may be negatively influenced by black race and alcohol abuse.
|
| |
|
|
|
|
|
