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591 Prevalence of antibodies to the HCV F (frameshift) protein in patients with chronic hepatitis C and the role of this protein in HCV infection
Category 5d." l~ral Hepatitis." Hepatitis C Clinical
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INSULIN RESISTANCE IS ASSOCIATED WITH HEPATIC STEATOSIS, BODY MASS INDEX AND OXIDATIVE STRESS SERUM MARKERS IN NON-3 GENOTYPE CHRONIC HEPATITIS C INFECTION
A.C. Oliveira I . A.L. Salgado 1, M.M.B. Leite-Mor 1, R.M. Catarino 1, K. Giavarotti 2, VB. Junqueira 2, E.R. Parise 1. 1Disciplina de
Gastroenterologia, Universidade Federal de Sg~o Paulo, S~o Paulo, Brazil, 2Disciplina de Geriatria, Universidade Federal de S6o Paulo, S~o Paulo, Brazil Background: Recent evidences suggest that insulin resistance (IR) is associated with fatty liver and fibrosis progression in patients with chronic hepatitis C (CHC). The exact mechanisms by wich IR can contribute to this fibrotic response remains to be elucitated. Aim: To correlate insulin resistance (IR) with demographic, biochemical, and histological findings arid serum parameters of oxidative stress in non 3 genotype CHC. Patients and Methods: 150 subjects with detectable HCV-RNA were submitted to liver biopsy. Fibrotic arid fifftammatory findings were scored according to Knodell et al. The genotype of the HCV-RNA was identified through restriction analysis of the amplified sequences of the noncoding 5/ region. Insulin and C-peptide concentrations were assayed by immunofluorimetry (Perldn Elmer BR-CS). IR index was calculated by the homeostasis model asseanlent (HOMA-IR). Patients with concurrent HBWHIV infections and alcohol intake >20 g]day were excluded from the study. In 60 CHC patients, with non 3 genotype, blood samples were also tested for determination of serum ferritin, glutathione and malondialdehyde (MDA) by enzymatic and colorimetric metho&, serum vitamin E, licopen and [)-carotene by HPLC, leptin serum levels by ari immunofluorimetric assay. Results: HOMA-IR values were significantly higher in CHC patients with non 3 genotypes (n= 105) than those with genotype 3 (n=45), (3.57+0.27 vs. 2.35+0.20, mean+SEM, respectively, p 0.001) and in non 3 genotype patients with (n= 59) than without (46) hepatic steatosis (4.30+0.39 vs. 2.44+0.27, p <0.001). Among the 60 non 3 genotype patients, there was a significative correlation (p < 0.05) of HOMA-IR values with BMI (rs 0.511), hepatic staging (rs 0.463) and inflammatory Knodell index (rs= 0.331), with C-peptide (rs=0.783), serum MDA (rs= 0.416) and glutathione (rs=-0.387). No significant correlation was found for HOMA and serum lepfin levels even when leptin was corrected by BMI. Multiple regression analysis identified BMI and MDA as independent predictors for insulin resistance in this population. Conelus|on: In these patients with CHC with non-3 genotype, insulin resistance is related to liver steatosis arid independently associated with BMI and serum markers of oxidative stress. Aeknowledgment: Research supported by" FAPESP (02/05260-6).
1
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COST-EFFECTIVENESS OF PEGINTERFERON a-2a (40 kDa) PLUS RIBAVIRIN IN TREATMENT OF CHRONIC HEPATITIS C (CHC) IN H I V - H C V CO-INFECTION
J. Hornberger 1'2'3, G. Carosi 4, M. Puoti 4, R. Bruno 5, J. Green 6, K.K. Patel 6, G. Giuliani 7. 1The SPHERE Institute~Acumen, LLC,
Burlingame, CA, USA," 2Depar#nent of Veterans Affairs, Palo Alto, CA, USA," SStanford University School of Medicine, Stanford, CA, USA; 4 Clinic'a di Malattie Infettioe e Tropic'all, Universitd di Brescia, A.O. Spedali Civili di Brescia, Brescia, Italy," 5Divisione Malattie Infettive e Tropicali, IRCCS Policlinico San Matteo Pavia, Pavia, Italy," 6Roche, Nutley, NJ, USA," 7Roche, Italy The recent AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) demonstrated the efficacy ofp eginterferon c~-2a plus rib avirin (RBV) and interferon a plus ribavirin (IFN/RBV) in patients co-infected with
215
HIV-HCM The cost-effectiveness of treating CHC with peginterferon O~-2a/RBV has not been assessed in this patient population. Methods: We developed a Markov Model of CHC disease progression in H W - H C V co-infection to assess the cost-effectiveness of peNnterferon 0~-2a/RBV compared with IFN/RBV Estimates of progression rates came from published studies. Treatment effect on sustained virological response (SVR) was based on findings from APRICOT. The analysis was a cohort of patients with mean age 40 years and H W - H C V co-infection. Mortality from H W was based on published results of an H W Swiss Cohort Study. Quality of life and costs for each health state were based on literature estimates and on the Italian health care setting. Costs in 2003 euros and benefits were discounted at 3 %. The Italian National Health Service (NHS) perspective was used. Results: In genotype 1 patients, quality-adjusted life years (QALYs) and costs increase with peginterferon 0~-2a/RBV relative to IFN/RBV by 0.76 and £7324, respectively. In genotype 2/3 patients, QALYs and costs increase by 1.44 years and £6222, respectively. In genotype 1 and 2/3 patients, peginterferon 0~-2a/RBV is cost-effective compared with IFN/RBV (genotype 1, £9684 per QALY gained; genotype 2/3 £4320 per QALY gained). Conclusions: Based on our model, peginterferon o~-2aTRBV is predicted to increase overall survival, and has cost-effectiveness ratios against IFN/RBV that are within acceptable ranges adopted by the NHS.
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PREVALENCE OF ANTIBODIES TO THE HCV F (FRAMESHIFT) PROTEIN IN PATIENTS WITH CHRONIC HEPATITIS C AND THE ROLE OF THIS PROTEIN IN HCV INFECTION
A. Miladi I , J.R Lavergne2, C. Hbzode I , D. Dhumeaux I , E Penin 2, J.M. Pawlotskv 1 . :Department of Virology, INSERM U635, and
Department of Hepatology and Gastroenterology, H@ital Henri Mondor, Universitd Paris 12, Crdteil, France," 2IBCP, CNRS UMR 5086, Lyon, FFa n c e
Alternative forms of genotype lb HCV core protein resulting from a +1 frameshift at codon 42, among which the F protein, have been recently identified. The frequency of such frameshiff events is unknown, as well as tile level of expression of the F protein in vivo, its immunogenicity and its potential role in the pathogenesis of HCV infection. We developed a sensitive and specific ELISA assay for the detection of anti-F protein (codons 43 141) antibodies and determined tile prevalence of such antibodies in 661 patients belonging to various populations. The assay is able to detect 2.2× 10 2 ng/microl of anti-F antibodies, with a specificity of 99.4%. Anti-F antibodies were found in 9.7% o f HCV-infected patients overall. The prevalence was of 12.3% in HCV genotype lb and 6.9% in HCV genotype 3, suggesting the existence of a frameshift protein in this genotype. Interestingly, 27.9% of patients with HCV genotype 3 infection and steatosis had anti-F antibodies, a finding that could indirectly indicate a role for the frameshifi, protein in HCV genotype 3a-induced steatosis. 17.4% of patients with hepatocelMar carcinoma had anti-F antibodies, as well as 20.0% of H B V - H C V coinfected patients and 30.2% of HIV-HCV coinfected patients, suggesting a possible role of a higher HCV RNA load in the emergence of anti-F antibodies. Conelusions: (i) The prevalence of anti-F antibodies in chronic hepatitis C is of the order of 10%. (ii) Frameshifts could occur in the core-coding sequence in HCV genotype 3a. (iii) Higher levels of F protein expression could be related to higher replication levels in HIV-HCV coinfected patients. (iv) The high prevalence of anti-F antibodies in HCV genotype 3a patients with steatosis raises the hypothesis of a role for this protein in hepatocellular lipid accumulation.
1•
INSULIN RESISTANCE IS ASSOCIATED WITH HEPATIC STEATOSIS, BODY MASS INDEX AND OXIDATIVE STRESS SERUM MARKERS IN NON-3 GENOTYPE CHRONIC HEPATITIS C INFECTION
A.C. Oliveira I . A.L. Salgado 1, M.M.B. Leite-Mor 1, R.M. Catarino 1, K. Giavarotti 2, VB. Junqueira 2, E.R. Parise 1. 1Disciplina de
Gastroenterologia, Universidade Federal de Sg~o Paulo, S~o Paulo, Brazil, 2Disciplina de Geriatria, Universidade Federal de S6o Paulo, S~o Paulo, Brazil Background: Recent evidences suggest that insulin resistance (IR) is associated with fatty liver and fibrosis progression in patients with chronic hepatitis C (CHC). The exact mechanisms by wich IR can contribute to this fibrotic response remains to be elucitated. Aim: To correlate insulin resistance (IR) with demographic, biochemical, and histological findings arid serum parameters of oxidative stress in non 3 genotype CHC. Patients and Methods: 150 subjects with detectable HCV-RNA were submitted to liver biopsy. Fibrotic arid fifftammatory findings were scored according to Knodell et al. The genotype of the HCV-RNA was identified through restriction analysis of the amplified sequences of the noncoding 5/ region. Insulin and C-peptide concentrations were assayed by immunofluorimetry (Perldn Elmer BR-CS). IR index was calculated by the homeostasis model asseanlent (HOMA-IR). Patients with concurrent HBWHIV infections and alcohol intake >20 g]day were excluded from the study. In 60 CHC patients, with non 3 genotype, blood samples were also tested for determination of serum ferritin, glutathione and malondialdehyde (MDA) by enzymatic and colorimetric metho&, serum vitamin E, licopen and [)-carotene by HPLC, leptin serum levels by ari immunofluorimetric assay. Results: HOMA-IR values were significantly higher in CHC patients with non 3 genotypes (n= 105) than those with genotype 3 (n=45), (3.57+0.27 vs. 2.35+0.20, mean+SEM, respectively, p 0.001) and in non 3 genotype patients with (n= 59) than without (46) hepatic steatosis (4.30+0.39 vs. 2.44+0.27, p <0.001). Among the 60 non 3 genotype patients, there was a significative correlation (p < 0.05) of HOMA-IR values with BMI (rs 0.511), hepatic staging (rs 0.463) and inflammatory Knodell index (rs= 0.331), with C-peptide (rs=0.783), serum MDA (rs= 0.416) and glutathione (rs=-0.387). No significant correlation was found for HOMA and serum lepfin levels even when leptin was corrected by BMI. Multiple regression analysis identified BMI and MDA as independent predictors for insulin resistance in this population. Conelus|on: In these patients with CHC with non-3 genotype, insulin resistance is related to liver steatosis arid independently associated with BMI and serum markers of oxidative stress. Aeknowledgment: Research supported by" FAPESP (02/05260-6).
1
•
COST-EFFECTIVENESS OF PEGINTERFERON a-2a (40 kDa) PLUS RIBAVIRIN IN TREATMENT OF CHRONIC HEPATITIS C (CHC) IN H I V - H C V CO-INFECTION
J. Hornberger 1'2'3, G. Carosi 4, M. Puoti 4, R. Bruno 5, J. Green 6, K.K. Patel 6, G. Giuliani 7. 1The SPHERE Institute~Acumen, LLC,
Burlingame, CA, USA," 2Depar#nent of Veterans Affairs, Palo Alto, CA, USA," SStanford University School of Medicine, Stanford, CA, USA; 4 Clinic'a di Malattie Infettioe e Tropic'all, Universitd di Brescia, A.O. Spedali Civili di Brescia, Brescia, Italy," 5Divisione Malattie Infettive e Tropicali, IRCCS Policlinico San Matteo Pavia, Pavia, Italy," 6Roche, Nutley, NJ, USA," 7Roche, Italy The recent AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT) demonstrated the efficacy ofp eginterferon c~-2a plus rib avirin (RBV) and interferon a plus ribavirin (IFN/RBV) in patients co-infected with
215
HIV-HCM The cost-effectiveness of treating CHC with peginterferon O~-2a/RBV has not been assessed in this patient population. Methods: We developed a Markov Model of CHC disease progression in H W - H C V co-infection to assess the cost-effectiveness of peNnterferon 0~-2a/RBV compared with IFN/RBV Estimates of progression rates came from published studies. Treatment effect on sustained virological response (SVR) was based on findings from APRICOT. The analysis was a cohort of patients with mean age 40 years and H W - H C V co-infection. Mortality from H W was based on published results of an H W Swiss Cohort Study. Quality of life and costs for each health state were based on literature estimates and on the Italian health care setting. Costs in 2003 euros and benefits were discounted at 3 %. The Italian National Health Service (NHS) perspective was used. Results: In genotype 1 patients, quality-adjusted life years (QALYs) and costs increase with peginterferon 0~-2a/RBV relative to IFN/RBV by 0.76 and £7324, respectively. In genotype 2/3 patients, QALYs and costs increase by 1.44 years and £6222, respectively. In genotype 1 and 2/3 patients, peginterferon 0~-2a/RBV is cost-effective compared with IFN/RBV (genotype 1, £9684 per QALY gained; genotype 2/3 £4320 per QALY gained). Conclusions: Based on our model, peginterferon o~-2aTRBV is predicted to increase overall survival, and has cost-effectiveness ratios against IFN/RBV that are within acceptable ranges adopted by the NHS.
I•
PREVALENCE OF ANTIBODIES TO THE HCV F (FRAMESHIFT) PROTEIN IN PATIENTS WITH CHRONIC HEPATITIS C AND THE ROLE OF THIS PROTEIN IN HCV INFECTION
A. Miladi I , J.R Lavergne2, C. Hbzode I , D. Dhumeaux I , E Penin 2, J.M. Pawlotskv 1 . :Department of Virology, INSERM U635, and
Department of Hepatology and Gastroenterology, H@ital Henri Mondor, Universitd Paris 12, Crdteil, France," 2IBCP, CNRS UMR 5086, Lyon, FFa n c e
Alternative forms of genotype lb HCV core protein resulting from a +1 frameshift at codon 42, among which the F protein, have been recently identified. The frequency of such frameshiff events is unknown, as well as tile level of expression of the F protein in vivo, its immunogenicity and its potential role in the pathogenesis of HCV infection. We developed a sensitive and specific ELISA assay for the detection of anti-F protein (codons 43 141) antibodies and determined tile prevalence of such antibodies in 661 patients belonging to various populations. The assay is able to detect 2.2× 10 2 ng/microl of anti-F antibodies, with a specificity of 99.4%. Anti-F antibodies were found in 9.7% o f HCV-infected patients overall. The prevalence was of 12.3% in HCV genotype lb and 6.9% in HCV genotype 3, suggesting the existence of a frameshift protein in this genotype. Interestingly, 27.9% of patients with HCV genotype 3 infection and steatosis had anti-F antibodies, a finding that could indirectly indicate a role for the frameshifi, protein in HCV genotype 3a-induced steatosis. 17.4% of patients with hepatocelMar carcinoma had anti-F antibodies, as well as 20.0% of H B V - H C V coinfected patients and 30.2% of HIV-HCV coinfected patients, suggesting a possible role of a higher HCV RNA load in the emergence of anti-F antibodies. Conelusions: (i) The prevalence of anti-F antibodies in chronic hepatitis C is of the order of 10%. (ii) Frameshifts could occur in the core-coding sequence in HCV genotype 3a. (iii) Higher levels of F protein expression could be related to higher replication levels in HIV-HCV coinfected patients. (iv) The high prevalence of anti-F antibodies in HCV genotype 3a patients with steatosis raises the hypothesis of a role for this protein in hepatocellular lipid accumulation.