Guest guest Posted March 8, 2011 Report Share Posted March 8, 2011 J Hepatol. 2011 Feb 24. [Epub ahead of print] Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients. Gane EJ, Rouzier R, Stedman C, Wiercinska-Drapalo A, Horban A, Chang L, Zhang Y, Sampeur P, Nájera I, P, Shulman NS, Tran JQ. Auckland Clinical Studies, New Zealand. Abstract BACKGROUND AND AIMS: Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients. METHODS: Thirty eligible patients were enrolled into 3 cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily. RESULTS: The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8 and -4.6 log(10) IU/mL in Cohorts 1, 2 and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15 HCV RNA was undetectable (<15 IU/mL) in 6/9 (67%), 4/8 (50%) and 8/8 (100%) patients in Cohorts 1, 2 and 3 respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100 mg and 200/100 mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations. CONCLUSIONS: Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r. Copyright © 2011. Published by Elsevier B.V. PMID: 21354234 [PubMed - as supplied by publisher] ------------------------------------------------------------------- J Hepatol. 2011 Feb 24. [Epub ahead of print] Naringenin Inhibits the Assembly and Long-Term Production of Infectious Hepatitis C Virus Particles Through a PPAR-Mediated Mechanism. Goldwasser J, Cohen PY, Lin W, Kitsberg D, Balaguer P, Polyak SJ, Chung RT, Yarmush ML, Nahmias Y. Center for Engineering in Medicine, Shriners Burns Hospital, Boston, MA; Harvard-MIT Division of Health Science and Technology, Cambridge, MA; Massachusetts General Hospital, Harvard Medical School, Boston, MA. Abstract BACKGROUND & AIMS: Hepatitis C virus (HCV) infection affects 3% of the world population and is the leading cause of chronic liver disease worldwide. Current standard of care is effective in only 50% of the patients, poorly tolerated and associated with significant side effects and viral resistance. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism and that its production is metabolically modulated. METHODS: The JFH1/Huh7.5.1 full lifecycle model of HCV was used to study the antiviral effects of naringenin on viral replication, assembly and production. Activation of PPARα was elucidated using GAL4-PPARα fusion reporters, PPRE reporters, qRT-PCR, and metabolic studies. Metabolic results were confirms in primary human hepatocytes. RESULTS: We demonstrate that the grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. We show that naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000 units of interferon. During the washout period, HCV levels returned to normal, consistent with our proposed mechanism of action. CONCLUSIONS: The data demonstrates that naringenin is a non-toxic assembly inhibitor of HCV, and that other PPARα agnoists play a similar role in blocking viral production. The combination of naringenin with STAT-C agents could potentially bring a rapid reduction in HCV levels during the early treatment phase, an outcome associated with sustained virological response. Copyright © 2011. Published by Elsevier B.V. PMID: 21354229 [PubMed - as supplied by publisher] ----------------------------------------------------------------- J Med Virol. 2011 Feb 23. doi: 10.1002/jmv.21788. [Epub ahead of print] Genotypes and viral load of hepatitis C virus among persons attending a voluntary counseling and testing center in Ethiopia. Abreha T, Woldeamanuel Y, Pietsch C, Maier M, Asrat D, Abebe A, Hailegiorgis B, Aseffa A, Liebert UG. Armauer Hansen Research Institute, Addis Ababa, Ethiopia; Faculty of Medicine, Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Addis Ababa, Ethiopia. tesfay95@.... Abstract The prevalence of different genotypes of hepatitis C virus (HCV) in Ethiopia is not known. HCV genotypes influence the response to therapy with alpha-interferon alone or in combination with ribavirin. A cross sectional study was conducted on attendees of voluntary counseling and testing center. Serum samples from 1,954 (734 HIV positive and 1,220 HIV negative) individuals were screened for HCV antibody. Active HCV infection was confirmed by quantitative PCR in 18 of the 71 samples with anti-HCV antibodies. The HCV viral load ranged from 39,650 to 9,878,341 IU/ml (median 1,589,631 IU/ml) with no significant difference [χ(2) (17) = 18.00, P = 0.389] between persons positive or negative for HIV. The viral load of HCV was, however, higher in older study subjects (r = 0.80, P = 0.000). HCV genotypes were determined using the VERSANT HCV Genotype Assay (LiPA) and sequence analysis of the NS5b region of the HCV genome. Diverse HCV genotypes were found including genotypes 1, 2, 4, and 5. There was no difference in the distribution regarding the HIV status. As in other parts of the world, genotyping of HCV must be considered whenever HCV is incriminated as a cause of hepatitis. J. Med. Virol. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc. PMID: 21351106 [PubMed - as supplied by publisher] ---------------------------------------------------------- J Virol. 2011 Mar 2. [Epub ahead of print] Immunodominance of HLA-A2 restricted hepatitis C virus-specific CD8+ T cell responses is linked to naive precursor frequency. Schmidt J, Neumann-Haefelin C, Altay T, Gostick E, Price DA, Lohmann V, Blum HE, Thimme R. Department of Medicine II, University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Germany; Department of Infection, Immunity and Biochemistry, Cardiff University School of Medicine, United Kingdom; Department of Molecular Virology, University of Heidelberg, Germany. Abstract The impact of naïve precursor frequency on human virus-specific CD8+ T cell immunodominance is not well understood. Using a recently developed MHC class I tetramer enrichment protocol, we found a conserved hierarchy and >10-fold difference in naïve precursor frequencies across three HLA-A2 restricted HCV-specific epitopes. Importantly, the NS31406 epitope with the highest naïve precursor frequency in healthy donors was also the most frequently targeted epitope in a large cohort of chronically HCV-infected patients, both ex vivo and after in vitro stimulation. These results indicate for the first time that immunodominance in a human viral infection is linked to naïve precursor frequency. PMID: 21367907 [PubMed - as supplied by publisher] Quote Link to comment Share on other sites More sharing options...
Guest guest Posted March 8, 2011 Report Share Posted March 8, 2011 J Hepatol. 2011 Feb 24. [Epub ahead of print] Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients. Gane EJ, Rouzier R, Stedman C, Wiercinska-Drapalo A, Horban A, Chang L, Zhang Y, Sampeur P, Nájera I, P, Shulman NS, Tran JQ. Auckland Clinical Studies, New Zealand. Abstract BACKGROUND AND AIMS: Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients. METHODS: Thirty eligible patients were enrolled into 3 cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily. RESULTS: The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8 and -4.6 log(10) IU/mL in Cohorts 1, 2 and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15 HCV RNA was undetectable (<15 IU/mL) in 6/9 (67%), 4/8 (50%) and 8/8 (100%) patients in Cohorts 1, 2 and 3 respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100 mg and 200/100 mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations. CONCLUSIONS: Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r. Copyright © 2011. Published by Elsevier B.V. PMID: 21354234 [PubMed - as supplied by publisher] ------------------------------------------------------------------- J Hepatol. 2011 Feb 24. [Epub ahead of print] Naringenin Inhibits the Assembly and Long-Term Production of Infectious Hepatitis C Virus Particles Through a PPAR-Mediated Mechanism. Goldwasser J, Cohen PY, Lin W, Kitsberg D, Balaguer P, Polyak SJ, Chung RT, Yarmush ML, Nahmias Y. Center for Engineering in Medicine, Shriners Burns Hospital, Boston, MA; Harvard-MIT Division of Health Science and Technology, Cambridge, MA; Massachusetts General Hospital, Harvard Medical School, Boston, MA. Abstract BACKGROUND & AIMS: Hepatitis C virus (HCV) infection affects 3% of the world population and is the leading cause of chronic liver disease worldwide. Current standard of care is effective in only 50% of the patients, poorly tolerated and associated with significant side effects and viral resistance. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism and that its production is metabolically modulated. METHODS: The JFH1/Huh7.5.1 full lifecycle model of HCV was used to study the antiviral effects of naringenin on viral replication, assembly and production. Activation of PPARα was elucidated using GAL4-PPARα fusion reporters, PPRE reporters, qRT-PCR, and metabolic studies. Metabolic results were confirms in primary human hepatocytes. RESULTS: We demonstrate that the grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. We show that naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000 units of interferon. During the washout period, HCV levels returned to normal, consistent with our proposed mechanism of action. CONCLUSIONS: The data demonstrates that naringenin is a non-toxic assembly inhibitor of HCV, and that other PPARα agnoists play a similar role in blocking viral production. The combination of naringenin with STAT-C agents could potentially bring a rapid reduction in HCV levels during the early treatment phase, an outcome associated with sustained virological response. Copyright © 2011. Published by Elsevier B.V. PMID: 21354229 [PubMed - as supplied by publisher] ----------------------------------------------------------------- J Med Virol. 2011 Feb 23. doi: 10.1002/jmv.21788. [Epub ahead of print] Genotypes and viral load of hepatitis C virus among persons attending a voluntary counseling and testing center in Ethiopia. Abreha T, Woldeamanuel Y, Pietsch C, Maier M, Asrat D, Abebe A, Hailegiorgis B, Aseffa A, Liebert UG. Armauer Hansen Research Institute, Addis Ababa, Ethiopia; Faculty of Medicine, Department of Microbiology, Immunology and Parasitology, Addis Ababa University, Addis Ababa, Ethiopia. tesfay95@.... Abstract The prevalence of different genotypes of hepatitis C virus (HCV) in Ethiopia is not known. HCV genotypes influence the response to therapy with alpha-interferon alone or in combination with ribavirin. A cross sectional study was conducted on attendees of voluntary counseling and testing center. Serum samples from 1,954 (734 HIV positive and 1,220 HIV negative) individuals were screened for HCV antibody. Active HCV infection was confirmed by quantitative PCR in 18 of the 71 samples with anti-HCV antibodies. The HCV viral load ranged from 39,650 to 9,878,341 IU/ml (median 1,589,631 IU/ml) with no significant difference [χ(2) (17) = 18.00, P = 0.389] between persons positive or negative for HIV. The viral load of HCV was, however, higher in older study subjects (r = 0.80, P = 0.000). HCV genotypes were determined using the VERSANT HCV Genotype Assay (LiPA) and sequence analysis of the NS5b region of the HCV genome. Diverse HCV genotypes were found including genotypes 1, 2, 4, and 5. There was no difference in the distribution regarding the HIV status. As in other parts of the world, genotyping of HCV must be considered whenever HCV is incriminated as a cause of hepatitis. J. Med. Virol. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc. PMID: 21351106 [PubMed - as supplied by publisher] ---------------------------------------------------------- J Virol. 2011 Mar 2. [Epub ahead of print] Immunodominance of HLA-A2 restricted hepatitis C virus-specific CD8+ T cell responses is linked to naive precursor frequency. Schmidt J, Neumann-Haefelin C, Altay T, Gostick E, Price DA, Lohmann V, Blum HE, Thimme R. Department of Medicine II, University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Germany; Department of Infection, Immunity and Biochemistry, Cardiff University School of Medicine, United Kingdom; Department of Molecular Virology, University of Heidelberg, Germany. Abstract The impact of naïve precursor frequency on human virus-specific CD8+ T cell immunodominance is not well understood. Using a recently developed MHC class I tetramer enrichment protocol, we found a conserved hierarchy and >10-fold difference in naïve precursor frequencies across three HLA-A2 restricted HCV-specific epitopes. Importantly, the NS31406 epitope with the highest naïve precursor frequency in healthy donors was also the most frequently targeted epitope in a large cohort of chronically HCV-infected patients, both ex vivo and after in vitro stimulation. These results indicate for the first time that immunodominance in a human viral infection is linked to naïve precursor frequency. PMID: 21367907 [PubMed - as supplied by publisher] Quote Link to comment Share on other sites More sharing options...
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