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Sa1067 Vitamin B12 Supplementation Improves Sustained-Viral-Response Rates in Hepatitis C Virus Genotype 1b-Infected Patients
Sa1067 Vitamin B12 Supplementation Improves Sustained-Viral-Response Rates in Hepatitis C Virus Genotype 1b-Infected Patients Alba Rocco, Debora Compare, Veronica Varriale, Olga Maria Nardone, Marco Sanduzzi Zamparelli, Gerardo Nardone Background: The primary goal of HCV therapy is to eliminate detectable circulating HCV. The combination of pegylated interferon (peg-IFN)-α and ribavirin, the current approved standard-of-care (SOC), eradicates the infection in only 45-50% of patients infected with HCV genotype 1 and up to 80% of those infected with genotypes 2 or 3. Approximately 50% of HCV-infected individuals do not clear the infection during the therapy or relapse at the end of the treatment stressing the need for more effective treatment. In Vitro studies have demonstrated that Vitamin B12, physiologically stored in high concentrations in the human liver, inhibits the translation of the HCV polyprotein by interfering with the internal ribosome entry site (IRES), a structure in the HCV 5'-nontranslated region. A recent retrospective study demonstrated that Vitamin serum B12 level predicted sustained viral response (SVR) in HCV-infected patients naïve to therapy treated with a combination of IFN and ribavirin. However, until now, no prospective studies have analyzed whether B12 supplementation could improve the rate of SVR. Aim: In this study, we evaluated the effect of vitamin B12 supplementation on SVR in patients with HCV-chronic hepatitis naïve to therapy. Material and methods: Sixty-four consecutive patients (32 male, mean age 50 yrs) with chronic HCV infection, naïve to therapy, were enrolled in the study. All patients underwent: routine biochemical evaluation, HCV-genotype and viral load assessment and percutaneous fine-needle liver biopsy. Histological diagnosis was made up according to Ishak criteria. Antiviral therapy consisted of pegylated IFN-α2a or α2b/weekly in combination with daily oral ribavirin. Patients were randomly assigned to receive Vitamin B12 supplementation (SOC + B12) for the period of therapy. Results: Twenty-eight patients were treated with SOC and 36 with SOC + B12. The 2 groups did not significantly differ according to age, sex, BMI, HCV-genotype, transaminase levels and histological parameters. Viral load was higher in patients treated with SOC + B12 (p <0.04) then in the SOC group. Side effect frequency did not differ between the groups except for anemia that was significantly more frequent in the SOC group (43% vs 18%, p <0.02). Dose reduction and therapy discontinuation were significantly more frequent in the SOC group then in SOC + B12 group (30% vs 13%, p <0.001 and 14% vs 9%, p<0.05, respectively). Interestingly, the rate of SVR was significantly higher in SOC + B12 patients then in SOC group for HCV genotype 1b (70% vs 25%, p<0.001) while it did not significantly differ in HCV genotype 2a/2c or 3a infected patients (91% vs 88%). Conclusion: Vitamin B12 supplementation significantly improves SVR rates in HCV genotype 1b-infected patients.
Sa1066
AASLD Abstracts
Response to Treatment in Chronic Hepatitis C Infection is Associated With Abrogation of Autoimmune Responses to Collagen: A Role for Autoimmunity in Liver Fibrosis Anil B. Seetharam, Vijay Subramanian, Thomas A. Kerr, Kevin M. Korenblat, Mauricio Lisker-Melman, Jeffrey S. Crippin, T. Mohanakumar Background: Treatment with pegylated interferon (Peg-IFN) and ribavirin has been shown to augment CD4+ T-helper 1 (Th1) responses and downregulate profibrotic and Th17 responses in chronic Hepatitis C virus (HCV) infection. Recently, antibodies (Abs) to extracellular matrix (ECM) collagen subtypes present in the liver have been shown to correlate with stage of fibrosis following HCV infection. A pathogenic role for autoimmunity to ECM collagen in inducing fibrosis and the effect of antiviral therapy on Abs to ECM collagen remains unknown. Aim: The objective of this study was to determine the effect of treatment with Peg-IFN alpha and ribavirin in a population of responders, non-responders, and treatment naïve patients on the level of Abs to liver specific ECM collagens. Methods: Patients with HCV viremia initiated on treatment with Peg-IFNα and with no pre-existing autoimmune disorder (n=20) were enrolled for analysis along with a cohort of infected patients with contraindication to therapy (n=10). Response to treatment was defined by achievement of sustained virologic response (SVR) while non-response was defined as failure to achieve SVR (relapse after end of treatment) and excluded subjects who discontinued therapy. Whole blood was collected at the end of treatment (48 weeks for genotype 1 and 24 weeks for genotype 2/3) and serum isolated. Enzyme linked immunosorbent assays (ELISAs) to collagen subtypes I, III, IV, and V as well as Vimentin were performed. Luminex multiplex bead immunoassays were used to assess peripheral cytokine levels. Differential patient demographics, cytokine profile, and ECM Ab subtype titers were determined with one-way analysis of variance with Bonferroni multiple comparison adjustment. Results: 30 patients were enrolled for this cross-sectional study: Responders (n=10), Non-Responders (n=10) and Treatment Naïve (n=10). No significant differences existed in age, ethnicity, gender, body mass index, viral genotype or load; or pre-treatment stage of fibrosis (Table 1). Responders to treatment showed significantly higher levels of circulating IFN-γ and lower levels of IL17 (p<0.05). Abs to collagen subtypes I, III, and V were significantly lower in responders compared to non-responders; who in turn had significantly lower levels than treatment naïve populations (p<0.05). Abs to collagen IV and Vimentin were not different among populations (Table 2). Conclusions: Antiviral therapy with peg IFNα and ribavirin is significantly associated with abrogation of autoimmunity to liver associated ECM collagen. This effect was most pronounced in responders to therapy by conventional treatment endpoints. Further study is warranted to evaluate the effects of antiviral therapy against HCV on Abs to ECM collagen to determine its pathogenic profibrotic role and to evaluate utility in guiding on-treatment management decisions. Table 1. Patient Demographics
Sa1068 An Intensive Educational Session and Multiple Focused Pre-Treatment Clinic Visits Can Improve SVR Rates Among Minority Veterans With Hepatitis C Joshua G. Vandersteen, Christian S. Jackson, Annette Hampton, Snorri Olafsson Background: Minority patients are known to have a higher prevalence of Hepatitis C (HCV) when compared to non-Hispanic Caucasians (nHC). This results in higher rates of complications such as cirrhosis and hepatocellular carcinoma in these populations when compared to nHC. In large studies SVR rates among genotype 1 (G1) African-Americans (AA) and Hispanics (H) are lower than G1 nHC. AA and H are more likely to discontinue treatment which impacts SVR and can result in the development of complications. Methods: Retrospective data was collected from a single VA facility for HCV treatment naïve patients from 20012011. Patients were evaluated based on race and ethnicity as well as genotype. Only patients with genotypes 1, 2 and 3 were included, since these were the majority of patients treated. These classifications were then compared to those achieving SVR and those who did not. Five patients who received monotherapy were excluded. All others were treated with interferon 2a or 2b and ribavirin. Prior to treatment patients were required to attend a one hour educational class followed by two clinic visits. After the second visit, laboratories and examinations were ordered. Once completed, treatment was ordered and all patients were scheduled for a two week visit, with 2-4 week follow-up. Results: Of the 257 treatment naïve patients who completed the initial pre-treatment evaluation, 68 (26%) were minorities and 189 (74%) nHC. 34 (13%) were African-American, 22 (9%) Hispanic, 5 Native Americans, 4 Hawaiian and 3 Asian. The overall SVR rate for all genotypes between minority and nHC was 41% and 49, respectively, p=0.29. 171 patients had genotype 1; 50 minorities and 119 nHC. For G1, the SVR was 36% for all minorities and 39% for nHC, p=0.75. Among the minorities the G1 SVR was 35% for AA (n=31) and 29% (n=14) for Hispanics. 88 patients had G2/ G3; 18 minorities and 70 nHC. The SVR for G1/G3 was 56% for minorities and 66% for nHC, p=0.42. Conclusion: The 41% SVR rate for all genotypes and 36% for G1 achieved for minority veterans is higher than in previous studies when compared to nHC veterans. The SVR rate of 35% for G1 AA was higher than previously reported in veteran and nonveteran populations. An intensive educational session and close follow up may be a cause for improved SVR in previously difficult to treat populations.
Table 2. Collagen Ab Levels Among Treatment Groups
Sa1069 Eosinophils After IFN Administration May Affect the Outcome of IFN Therapy in Chronic Hepatitis C Patients Yasuhiro Tsuda, Hideo Fukui, Shinya Fukunishi, Yusuke Tsuchimoto, Akira Asai, Katsuhiko Miyaji, Akira Fukuda, Kazuhide Higuchi Background: Since the identification of single nucleotide polymorphisms located to the type III interferon (IFN) lambda gene as the efficacy predictor of IFN therapy, host factors of IFN therapy for patients with chronic hepatitis C (CHC) begins to focus again. Because IFN-lambda leads host to Th1 responses and inhibits Th2 responses, it is possible that CHC patients unresponsive to IFN therapy may be poor at a shift to Th1 responses after IFN administration. Th2 cells elicit eosinophils and monocytes are stimulated by Th1 responses. Therefore we focused on the kinetics of blood cells after IFN administration. Especially, the relationship between monocytes or eosinophils and IFN responses were investigated.
antibody level expressed in ng/mL with ± SEM
AASLD Abstracts
S-960
Sa1066
AASLD Abstracts
Response to Treatment in Chronic Hepatitis C Infection is Associated With Abrogation of Autoimmune Responses to Collagen: A Role for Autoimmunity in Liver Fibrosis Anil B. Seetharam, Vijay Subramanian, Thomas A. Kerr, Kevin M. Korenblat, Mauricio Lisker-Melman, Jeffrey S. Crippin, T. Mohanakumar Background: Treatment with pegylated interferon (Peg-IFN) and ribavirin has been shown to augment CD4+ T-helper 1 (Th1) responses and downregulate profibrotic and Th17 responses in chronic Hepatitis C virus (HCV) infection. Recently, antibodies (Abs) to extracellular matrix (ECM) collagen subtypes present in the liver have been shown to correlate with stage of fibrosis following HCV infection. A pathogenic role for autoimmunity to ECM collagen in inducing fibrosis and the effect of antiviral therapy on Abs to ECM collagen remains unknown. Aim: The objective of this study was to determine the effect of treatment with Peg-IFN alpha and ribavirin in a population of responders, non-responders, and treatment naïve patients on the level of Abs to liver specific ECM collagens. Methods: Patients with HCV viremia initiated on treatment with Peg-IFNα and with no pre-existing autoimmune disorder (n=20) were enrolled for analysis along with a cohort of infected patients with contraindication to therapy (n=10). Response to treatment was defined by achievement of sustained virologic response (SVR) while non-response was defined as failure to achieve SVR (relapse after end of treatment) and excluded subjects who discontinued therapy. Whole blood was collected at the end of treatment (48 weeks for genotype 1 and 24 weeks for genotype 2/3) and serum isolated. Enzyme linked immunosorbent assays (ELISAs) to collagen subtypes I, III, IV, and V as well as Vimentin were performed. Luminex multiplex bead immunoassays were used to assess peripheral cytokine levels. Differential patient demographics, cytokine profile, and ECM Ab subtype titers were determined with one-way analysis of variance with Bonferroni multiple comparison adjustment. Results: 30 patients were enrolled for this cross-sectional study: Responders (n=10), Non-Responders (n=10) and Treatment Naïve (n=10). No significant differences existed in age, ethnicity, gender, body mass index, viral genotype or load; or pre-treatment stage of fibrosis (Table 1). Responders to treatment showed significantly higher levels of circulating IFN-γ and lower levels of IL17 (p<0.05). Abs to collagen subtypes I, III, and V were significantly lower in responders compared to non-responders; who in turn had significantly lower levels than treatment naïve populations (p<0.05). Abs to collagen IV and Vimentin were not different among populations (Table 2). Conclusions: Antiviral therapy with peg IFNα and ribavirin is significantly associated with abrogation of autoimmunity to liver associated ECM collagen. This effect was most pronounced in responders to therapy by conventional treatment endpoints. Further study is warranted to evaluate the effects of antiviral therapy against HCV on Abs to ECM collagen to determine its pathogenic profibrotic role and to evaluate utility in guiding on-treatment management decisions. Table 1. Patient Demographics
Sa1068 An Intensive Educational Session and Multiple Focused Pre-Treatment Clinic Visits Can Improve SVR Rates Among Minority Veterans With Hepatitis C Joshua G. Vandersteen, Christian S. Jackson, Annette Hampton, Snorri Olafsson Background: Minority patients are known to have a higher prevalence of Hepatitis C (HCV) when compared to non-Hispanic Caucasians (nHC). This results in higher rates of complications such as cirrhosis and hepatocellular carcinoma in these populations when compared to nHC. In large studies SVR rates among genotype 1 (G1) African-Americans (AA) and Hispanics (H) are lower than G1 nHC. AA and H are more likely to discontinue treatment which impacts SVR and can result in the development of complications. Methods: Retrospective data was collected from a single VA facility for HCV treatment naïve patients from 20012011. Patients were evaluated based on race and ethnicity as well as genotype. Only patients with genotypes 1, 2 and 3 were included, since these were the majority of patients treated. These classifications were then compared to those achieving SVR and those who did not. Five patients who received monotherapy were excluded. All others were treated with interferon 2a or 2b and ribavirin. Prior to treatment patients were required to attend a one hour educational class followed by two clinic visits. After the second visit, laboratories and examinations were ordered. Once completed, treatment was ordered and all patients were scheduled for a two week visit, with 2-4 week follow-up. Results: Of the 257 treatment naïve patients who completed the initial pre-treatment evaluation, 68 (26%) were minorities and 189 (74%) nHC. 34 (13%) were African-American, 22 (9%) Hispanic, 5 Native Americans, 4 Hawaiian and 3 Asian. The overall SVR rate for all genotypes between minority and nHC was 41% and 49, respectively, p=0.29. 171 patients had genotype 1; 50 minorities and 119 nHC. For G1, the SVR was 36% for all minorities and 39% for nHC, p=0.75. Among the minorities the G1 SVR was 35% for AA (n=31) and 29% (n=14) for Hispanics. 88 patients had G2/ G3; 18 minorities and 70 nHC. The SVR for G1/G3 was 56% for minorities and 66% for nHC, p=0.42. Conclusion: The 41% SVR rate for all genotypes and 36% for G1 achieved for minority veterans is higher than in previous studies when compared to nHC veterans. The SVR rate of 35% for G1 AA was higher than previously reported in veteran and nonveteran populations. An intensive educational session and close follow up may be a cause for improved SVR in previously difficult to treat populations.
Table 2. Collagen Ab Levels Among Treatment Groups
Sa1069 Eosinophils After IFN Administration May Affect the Outcome of IFN Therapy in Chronic Hepatitis C Patients Yasuhiro Tsuda, Hideo Fukui, Shinya Fukunishi, Yusuke Tsuchimoto, Akira Asai, Katsuhiko Miyaji, Akira Fukuda, Kazuhide Higuchi Background: Since the identification of single nucleotide polymorphisms located to the type III interferon (IFN) lambda gene as the efficacy predictor of IFN therapy, host factors of IFN therapy for patients with chronic hepatitis C (CHC) begins to focus again. Because IFN-lambda leads host to Th1 responses and inhibits Th2 responses, it is possible that CHC patients unresponsive to IFN therapy may be poor at a shift to Th1 responses after IFN administration. Th2 cells elicit eosinophils and monocytes are stimulated by Th1 responses. Therefore we focused on the kinetics of blood cells after IFN administration. Especially, the relationship between monocytes or eosinophils and IFN responses were investigated.
antibody level expressed in ng/mL with ± SEM
AASLD Abstracts
S-960