- Email: [email protected]
912 APOLIPOPROTEIN E4 ALLELE PROTECTS FROM CHRONIC HCV INFECTION
POSTERS 911 HOST LIPID RESPONSE TO HCV INFECTION: CHANGES IN LIPID LEVELS BEFORE, DURING, AND AFTER ACUTE HCV INFECTION M. Morris1 , J. Evans1 , A. Asher1 , K. Maher1 , K. Page1 , J. McCarthy1,2 . 1 Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, 2 Institute for Genome Sciences and Policy, Duke University, Durham, NC, USA E-mail: [email protected] Background and Aims: Understanding lipid disturbances during acute hepatitis C (HCV) infection may shed light on the mechanism of viral pathogenesis and HCV-associated disease progression. The overall aim of this study was to characterize host lipid response to HCV during acute infection and its effect on spontaneous clearance. Methods: We examined changes in lipid levels across HCV events using preliminary data from 26 young injection drug users (IDU) enrolled in a prospective study of incident HCV infection in San Francisco, CA, USA. Outcomes included HCV acute infection and spontaneous resolution. HDL and LDL cholesterol, triglycerides, ApoA1, ApoB, ApoCIII, and ApoE levels were measured using immunoturbidimetric tests. To account for varying periods of time between pre- and post-infection a mean percent change (MPC) in lipid levels across events was calculated. We examined trends in lipoproteins before and after HCV infection and assessed differences between spontaneous resolvers and those who progressed to chronic infection using t-tests. Results: Acutely infected IDU (n = 12) had lower pre-infection lipid levels compared to exposed non-infected IDU (n = 14); with significantly lower levels of ApoA1 (mean: 131 mg/dL vs. 154 mg/dL, p = 0.03) and somewhat lower levels of total cholesterol (167 mg/dL vs. 197 mg/dL, p = 0.09) and ApoB (mean: 74 mg/dL vs. 91 mg/dL, p-value: 0.09). Among 12 (46%) subjects with pre- and duringinfection lipid levels, resolvers demonstrated a reduction in total cholesterol (MPC: −0.23 vs. 0.08, p = 0.04), HDL (MPC: −0.18 vs. 0.22, p = 0.09), LDL (MPC: −0.25 vs. 0.27, p = 0.05), ApoA1 (MPC: −0.15 vs. 0.12, p = 0.1), ApoB (MPC: −0.19 vs. 0.11, p = 0.08) and ApoCIII (MPC: −0.36 vs. −0.0044, p = 0.1) compared to chronically infected. Among 4 (15%) resolvers, post-resolution all lipoproteins rebounded to preinfection levels. Conclusion: These preliminary findings suggest that while higher ApoA1 levels may protect against initial HCV infection, a reduction in ApoA1, and other lipoprotein levels, during infection may play a role in spontaneous resolution. Pre-infection data from 170 IDU, and post-infection data from 83 IDU, available January 2012 will allow us to examine longitudinal changes in lipid levels before, during, and after HCV infection associated with infection outcomes. 912 APOLIPOPROTEIN E4 ALLELE PROTECTS FROM CHRONIC HCV INFECTION 1 2 2 T. Muller ¨ , J. Fischer2 , J. Rosendahl2 , S. Bohm ¨ , F. van Bommel ¨ , 2 3 4 4 5 J. Wiegand , R. Gessner , V. Weich , C. Sarrazin , H. Witt , A. Bergk1 , E. Schott1 , B. Wiedenmann1 , T. Berg2 . 1 Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charit´e Universit¨ atsmedizin Berlin, Campus Virchow Klinikum, Berlin, 2 Klinik und Poliklinik f¨ ur Gastroenterologie und Rheumatologie, Sektion Hepatologie, Universit¨ atsklinikum Leipzig, 3 Klinik f¨ ur Visceral-, Transplantations-, Thorax- und Gef¨ aßchirurgie, Universit¨ atsklinikum Leipzig, Leipzig, 4 Medizinische Klinik I, Universit¨ atsklinikum der Johann-WolfgangGoethe-Universit¨ at, Frankfurt/Main, 5 Kinderklinik und Poliklinik, Technische Universit¨ at M¨ unchen (TUM), M¨ unchen, Germany E-mail: [email protected] Background and Aims: Host genetic single nucleotide polymorphisms (SNPs) have been shown to influence the outcome of HCV infection. Infectious HCV particles bind to host lipoproteins such as low-density lipoproteins (LDL) and low-density lipoprotein
receptors (LDLR) have been termed candidate receptors for hepatocellular uptake of HCV-LDL complexes. Common SNPs in the gene encoding apolipoprotein E (apoE) – a major structural LDL component and natural ligand of LDLR – have been associated with spontaneous resolution of HCV infection, severity of histological liver damage and response to therapy in chronic HCV infection. We wanted to further investigate the role of apoE polymorphisms in two large and independent cohorts of patients with chronic HCV infection and healthy and diseased control patients. Patients and Methods: We determined the prevalence of apoE genotypes and apoE alleles in 701 and 295 chronically HCV-infected patients, 2234 healthy controls and 283 individuals with non-HCV associated chronic liver disease. We also assessed the influence of apoE SNPs on the severity of histological inflammation and fibrosis in 555 liver biopsies from chronically HCV-infected patients. Results: The comparison of apoE allele proportions in chronically HCV-infected patients revealed significant differences in comparison to healthy controls (p = 0.007). This was primarily due to a substantial under-representation of the apoE4 allele in chronically HCV-infected patients (10.5% respectively 9.5%) vs. 13.1% in healthy controls (p = 0.001) and apoE4 allele positive genotypes (20% apoE(+) respectively 18% apoE(+) in HCV-infected patients vs. 24.5% apoE(+) in healthy controls; p = 0.001). ApoE4 allele and apoE4(+) genotype distribution in patients with nonHCV associated chronic liver disease were very similar to healthy controls (14% respectively 26.9%, p = 0.421) and also differed from chronically HCV-infected patients (p = 0.012 for apoE4 allele and p = 0.008 for apoE4(+) genotypes). Except for total cholesterol, clinical parameters did not differ among apoE4(−) and apoE4(+) genotypes. The apoE4 allele frequency was increased in chronically HCV-infected patients with histological mild liver disease but very similar for severe hepatic fibrosis and inflammation. Conclusions: The under-representation of the apoE4 allele in chronically HCV-infected patients suggests a decreased susceptibility to chronic HCV infection in apoE4 allele carriers, most likely due to alterations of the host lipoprotein metabolism. 913 USING SHORT-TERM MONOTHERAPY AND IN VITRO DATA TO MAKE EARLY PREDICTIONS OF CLINICAL HCV RESPONSE: EXAMPLES FROM MK-5172, A SECOND GENERATION HCV NS3/4A PROTEASE INHIBITOR R.B. Nachbar1 , J.A. Stone1 , A. Petry2 , B. Poland3 , L. Caro4 , L.A. Wenning1 , A. Khan1 , J. Palcza5 , K. Van Dyck6 , I. Fraser2 , N. Mobashery7 , E. O’Mara2 . 1 Modeling and Simulation, 2 Clinical Pharmacology, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 3 Pharsight Corp., Sunnyvale, CA, 4 Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, 5 Early Clinical Development Statistics, 6 Clinical Pharmacology Europe, 7 Late Stage Development Hepatology, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA E-mail: [email protected] Background and Aims: A placebo-controlled 7-day monotherapy study of MK-5172 in treatment-naïve patients with chronic genotype (GT) 1 or 3 HCV infection, showed a similar robust reduction of viral load over a broad range of doses (50– 800 mg QD) in GT1 patients and a dose-dependent response in GT3 patients (100–800 mg QD). On-treatment viral breakthrough was not observed. This analysis investigated a novel approach of viral dynamics modeling utilizing the early monotherapy response data and in vitro potency data to predict clinical response. Methods: A dose-response single-species viral dynamics model for GT3 patients was developed. Consistency of the relative potency (ratio of GT1/GT3 ED50 ) in vivo to that observed in vitro (ratio of protease IC50 s) was tested through fitting of the GT1 data under a fixed relative potency from the in vitro data. Similarly, a 2-species viral model was developed by assuming relative
Journal of Hepatology 2012 vol. 56 | S225–S388
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receptors (LDLR) have been termed candidate receptors for hepatocellular uptake of HCV-LDL complexes. Common SNPs in the gene encoding apolipoprotein E (apoE) – a major structural LDL component and natural ligand of LDLR – have been associated with spontaneous resolution of HCV infection, severity of histological liver damage and response to therapy in chronic HCV infection. We wanted to further investigate the role of apoE polymorphisms in two large and independent cohorts of patients with chronic HCV infection and healthy and diseased control patients. Patients and Methods: We determined the prevalence of apoE genotypes and apoE alleles in 701 and 295 chronically HCV-infected patients, 2234 healthy controls and 283 individuals with non-HCV associated chronic liver disease. We also assessed the influence of apoE SNPs on the severity of histological inflammation and fibrosis in 555 liver biopsies from chronically HCV-infected patients. Results: The comparison of apoE allele proportions in chronically HCV-infected patients revealed significant differences in comparison to healthy controls (p = 0.007). This was primarily due to a substantial under-representation of the apoE4 allele in chronically HCV-infected patients (10.5% respectively 9.5%) vs. 13.1% in healthy controls (p = 0.001) and apoE4 allele positive genotypes (20% apoE(+) respectively 18% apoE(+) in HCV-infected patients vs. 24.5% apoE(+) in healthy controls; p = 0.001). ApoE4 allele and apoE4(+) genotype distribution in patients with nonHCV associated chronic liver disease were very similar to healthy controls (14% respectively 26.9%, p = 0.421) and also differed from chronically HCV-infected patients (p = 0.012 for apoE4 allele and p = 0.008 for apoE4(+) genotypes). Except for total cholesterol, clinical parameters did not differ among apoE4(−) and apoE4(+) genotypes. The apoE4 allele frequency was increased in chronically HCV-infected patients with histological mild liver disease but very similar for severe hepatic fibrosis and inflammation. Conclusions: The under-representation of the apoE4 allele in chronically HCV-infected patients suggests a decreased susceptibility to chronic HCV infection in apoE4 allele carriers, most likely due to alterations of the host lipoprotein metabolism. 913 USING SHORT-TERM MONOTHERAPY AND IN VITRO DATA TO MAKE EARLY PREDICTIONS OF CLINICAL HCV RESPONSE: EXAMPLES FROM MK-5172, A SECOND GENERATION HCV NS3/4A PROTEASE INHIBITOR R.B. Nachbar1 , J.A. Stone1 , A. Petry2 , B. Poland3 , L. Caro4 , L.A. Wenning1 , A. Khan1 , J. Palcza5 , K. Van Dyck6 , I. Fraser2 , N. Mobashery7 , E. O’Mara2 . 1 Modeling and Simulation, 2 Clinical Pharmacology, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 3 Pharsight Corp., Sunnyvale, CA, 4 Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, 5 Early Clinical Development Statistics, 6 Clinical Pharmacology Europe, 7 Late Stage Development Hepatology, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA E-mail: [email protected] Background and Aims: A placebo-controlled 7-day monotherapy study of MK-5172 in treatment-naïve patients with chronic genotype (GT) 1 or 3 HCV infection, showed a similar robust reduction of viral load over a broad range of doses (50– 800 mg QD) in GT1 patients and a dose-dependent response in GT3 patients (100–800 mg QD). On-treatment viral breakthrough was not observed. This analysis investigated a novel approach of viral dynamics modeling utilizing the early monotherapy response data and in vitro potency data to predict clinical response. Methods: A dose-response single-species viral dynamics model for GT3 patients was developed. Consistency of the relative potency (ratio of GT1/GT3 ED50 ) in vivo to that observed in vitro (ratio of protease IC50 s) was tested through fitting of the GT1 data under a fixed relative potency from the in vitro data. Similarly, a 2-species viral model was developed by assuming relative
Journal of Hepatology 2012 vol. 56 | S225–S388
S355