THE NORTH CAROLINA HEPATITIS BETA CLINICAL RESEARCH NETWORK
Michael W Fried, Professor
University Of North Carolina Chapel Hill, Office Of Sponsored Research, Chapel Hill, Nc 27599
Grant 5U01DK082867-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The optimal treatment for chronic hepatitis B remains controversial. Published guidelines from several sources suggest initiating antiviral therapy, in general, when serum ALT activity is abnormal and when significant liver disease is present. These recommendations have largely been developed by balancing the likelihood of response as measured in short-term studies against the likelihood of developing viral resistance during extended therapy. However, these guidelines have never been prospectively evaluated to determine whether they truly represent the best strategy for selecting candidates for treatment. Furthermore, recent epidemiologic data indicate that the presence of high level HBV viremia itself is an important risk factor for subsequent cirrhosis and hepatocellular carcinoma, suggesting that rigid adherence to treatment guidelines may disadvantage many patients for whom long-term viral suppression may be beneficial. The current availability of multiple potent antiviral agents with good safety profiles and a seemingly low risk of resistance provide an opportunity to optimize strategies to treat chronic hepatitis B. This proposal will focus on the design of 1) a research database and specimen repository and 2) a collaborative multicenter trial to corroborate current treatment guidelines while comparing the long-term efficacy and safety of monotherapy vs. combination therapy. The study design will further refine the identification and management of hepatitis B viral resistance during extended therapy, and provide important information regarding the long-term outcomes associated with treatment. Our proposal to participate as a Clinical Center for this cooperative study will emphasize the experience, unique attributes, and patient population of the Liver Program at the University of North Carolina at Chapel Hill, in collaboration with Duke University, and Carolinas Medical Center, which will ensure successful completion of these studies as a member of the Hepatitis B Clinical Research network
Keywords: 9-(2-phosphonomethoxypropyl)adenine; 9-(2-phosphonylmethoxypropyl)adenine; 9-PMPA; Active Follow-up; Adherence; Adherence (attribute); Anti-Viral Response; Antiviral Agents; Antiviral Drugs; Antiviral Response; Antiviral Therapy; Antiviral resistance; Antiviral resistant; Antivirals; Appearance; Arm; Assay; Australia Antigen; Bioassay; Biologic Assays; Biological Assay; Blood Serum; Body Tissues; Carcinoma of the Liver Cells; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Combined Modality Therapy; Comorbidity; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Detection; Disadvantaged; Disease Progression; Drugs; ELIG; Eligibility; Eligibility Determination; Enrollment; Ensure; Equilibrium; Ethics Committees, Research; Evolution; Future; Genetic Alteration; Genetic Change; Genetic defect; Guidelines; HBV; HBV Chronic Infection; HBeAg; HBsAg; HBsAg (hepatitis B surface antigen); HCC; HIPAA; Health Insurance Portability and Accountability Act; Hepatic Disorder; Hepatitis; Hepatitis B; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Therapy; Hepatitis B Treatment; Hepatitis B Virus; Hepatitis B e Antigens; Hepatitis B, Chronic; Hepatitis Be Antigens; Hepatitis Virus, Homologous Serum; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; IRBs; Immunology; Immunology (Including BRMP); Immunology (NCI Program); Incidence; Individual; Institutional Review Boards; Kennedy Kassebaum Act; Liver; Liver diseases; Longitudinal Studies; Measures; Medical; Medical center; Medication; Methods; Minor; Multicenter Trials; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; Mutation; Natural History; North Carolina; Outcome; PBMC; PL 104-191; PL104-191; Participant; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Population; Primary carcinoma of the liver cells; Principal Investigator; Programs (PT); Programs [Publication Type]; Protocol; Protocol Screening; Protocols documentation; Protocols, Treatment; Public Law 104-191; Publishing; RGM; Race; Racial Group; Recommendation; Regimen; Registries; Relative; Relative (related person); Research; Research Design; Research Ethics Committees; Research Specimen; Resistance; Resistance development; Resistant development; Risk; Risk Factors; Role; Safety; Sampling; Science of Virology; Serologic; Serological; Serum; Site; Source; Specimen; Stocks, Racial; Study Type; Tenofovir; Testing; Therapeutic; Tissues; Treatment Protocols; Treatment Regimen; Treatment Schedule; United States Health Insurance Portability and Accountability Act; Universities; Upper arm; Variant; Variation; Viral; Viral Hepatitis B; Viremia; Virology; Virus; Viruses, General; anti-viral resistance; anti-viral resistant; balance; balance function; body system, hepatic; clinical data repository; clinical data warehouse; clinical investigation; cohort; combination therapy; combined modality treatment; combined treatment; cooperative study; data repository; design; designing; developing resistance; drug/agent; e Antigens; enroll; entecavir; epidemiologic data; experience; follow-up; genome mutation; hepatitis associated antigen; hepatopathy; insight; intervention development; intrahepatic; liver disorder; long-term study; meetings; member; multimodality therapy; novel; novel marker; organ system, hepatic; patient population; prevent; preventing; programs; relational database; repository; resistance to anti-viral; resistance to antiviral; resistant; resistant to anti-viral; resistant to antiviral; response; serum hepatitis; sharing data; social role; study design; therapy development; translational study; treatment development; treatment of viral infectious disease; viraemia; viral resistance; viral sepsis; virology; virusemia
Project start date: 2008-09-30
Project end date: 2015-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2010
PFA/PA: RFA-DK-07-011
5U01DK082867-02 (2009): $415945
Sponsored Links Excellgen http://Excellgen.com
THE NORTH CAROLINA HEPATITIS BETA CLINICAL RESEARCH NETWORK
Michael W Fried
University Of North Carolina Chapel Hill, Office Of Sponsored Research, Chapel Hill, Nc 27599
Grant 5U01DK082867-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The optimal treatment for chronic hepatitis B remains controversial. Published guidelines from several sources suggest initiating antiviral therapy, in general, when serum ALT activity is abnormal and when significant liver disease is present. These recommendations have largely been developed by balancing the likelihood of response as measured in short-term studies against the likelihood of developing viral resistance during extended therapy. However, these guidelines have never been prospectively evaluated to determine whether they truly represent the best strategy for selecting candidates for treatment. Furthermore, recent epidemiologic data indicate that the presence of high level HBV viremia itself is an important risk factor for subsequent cirrhosis and hepatocellular carcinoma, suggesting that rigid adherence to treatment guidelines may disadvantage many patients for whom long-term viral suppression may be beneficial. The current availability of multiple potent antiviral agents with good safety profiles and a seemingly low risk of resistance provide an opportunity to optimize strategies to treat chronic hepatitis B. This proposal will focus on the design of 1) a research database and specimen repository and 2) a collaborative multicenter trial to corroborate current treatment guidelines while comparing the long-term efficacy and safety of monotherapy vs. combination therapy. The study design will further refine the identification and management of hepatitis B viral resistance during extended therapy, and provide important information regarding the long-term outcomes associated with treatment. Our proposal to participate as a Clinical Center for this cooperative study will emphasize the experience, unique attributes, and patient population of the Liver Program at the University of North Carolina at Chapel Hill, in collaboration with Duke University, and Carolinas Medical Center, which will ensure successful completion of these studies as a member of the Hepatitis B Clinical Research network
Keywords: 9-(2-phosphonomethoxypropyl)adenine; 9-(2-phosphonylmethoxypropyl)adenine; 9-PMPA; Active Follow-up; Adherence; Adherence (attribute); Anti-Viral Response; Antiviral Agents; Antiviral Drugs; Antiviral Response; Antiviral Therapy; Antiviral resistance; Antiviral resistant; Antivirals; Appearance; Assay; Australia Antigen; Bioassay; Biologic Assays; Biological Assay; Blood Serum; Body Tissues; Carcinoma of the Liver Cells; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Combined Modality Therapy; Comorbidity; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Detection; Disadvantaged; Disease Progression; Drugs; ELIG; Eligibility; Eligibility Determination; Enrollment; Ensure; Equilibrium; Ethics Committees, Research; Evolution; Future; Genetic Alteration; Genetic Change; Genetic defect; Guidelines; HBV; HBV Chronic Infection; HBeAg; HBsAg; HBsAg (hepatitis B surface antigen); HCC; HIPAA; Health Insurance Portability and Accountability Act; Hepatic Disorder; Hepatitis; Hepatitis B; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Therapy; Hepatitis B Treatment; Hepatitis B Virus; Hepatitis B e Antigens; Hepatitis B, Chronic; Hepatitis Be Antigens; Hepatitis Virus, Homologous Serum; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; IRBs; Immunology; Immunology (Including BRMP); Immunology (NCI Program); Incidence; Individual; Institutional Review Boards; Kennedy Kassebaum Act; Liver; Liver diseases; Longitudinal Studies; Measures; Medical; Medical center; Medication; Methods; Minor; Multicenter Trials; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; Mutation; Natural History; North Carolina; Outcome; PBMC; PL 104-191; PL104-191; Participant; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Population; Primary carcinoma of the liver cells; Principal Investigator; Programs (PT); Programs [Publication Type]; Protocol; Protocol Screening; Protocols documentation; Public Law 104-191; Publishing; Race; Racial Group; Recommendation; Regimen; Registries; Relative; Relative (related person); Research; Research Design; Research Ethics Committees; Research Specimen; Resistance; Resistance development; Resistant development; Risk; Risk Factors; Role; Safety; Sampling; Science of Virology; Serologic; Serological; Serum; Site; Source; Specimen; Stocks, Racial; Study Type; Tenofovir; Testing; Therapeutic; Tissues; United States Health Insurance Portability and Accountability Act; Universities; Variant; Variation; Viral; Viral Hepatitis B; Viremia; Virology; Virus; Viruses, General; anti-viral resistance; anti-viral resistant; arm; balance; balance function; body system, hepatic; clinical data repository; clinical data warehouse; clinical investigation; cohort; combination therapy; combined modality treatment; combined treatment; cooperative study; data repository; design; designing; developing resistance; drug/agent; e Antigens; enroll; entecavir; epidemiologic data; experience; follow-up; genome mutation; hepatitis associated antigen; hepatopathy; insight; intervention development; intrahepatic; liver disorder; long-term study; meetings; member; multimodality therapy; novel; novel marker; organ system, hepatic; patient population; prevent; preventing; programs; relational database; repository; resistance to anti-viral; resistance to antiviral; resistant; resistant to anti-viral; resistant to antiviral; response; serum hepatitis; sharing data; social role; study design; therapy development; translational study; treatment development; treatment of viral infectious disease; viraemia; viral resistance; viral sepsis; virology; virusemia
Project start date: 2008-09-30
Project end date: 2015-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: RFA-DK-07-011
5U01DK082867-03 (2010): $320450
Grants awarded to Michael W Fried
FAMCICLOVIR FOR CHRONIC HEPATITIS B
Michael W Fried, Associate Professor Of Medicine
Emory University 1599 Clifton Road, 4th Floor Atlanta, Ga 30322
Grant 5M01RR000039-370546 from National Center For Research Resources
Abstract: This is a double blind, parallel group, placebo controlled, multicenter, phase IIIA study to evaluate the pharmacokinetics of Famciclovir for the treatment of chronic hepatitis B in patients who are HBeAg positive. It seeks to understand the effects of chronic active hapatitis on the ability to metabolize and/or clear the antiviral therapy.
Keywords: antiviral agent, chronic disease /disorder, drug screening /evaluation, hepatitis B, human therapy evaluation, liver disorder chemotherapy, liver pharmacology, pharmacokinetics, clinical trial phase II /III /IV, clinical research, human subject
HEPATITIS C IN CLINICALLY DISCORDANT HEMOPHILIC SIBLINGS
Michael W Fried, Associate Professor Of Medicine
Medicineuniversity Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 5R01HL064817-03 from National Heart, Lung, And Blood Institute IRG: ZDK1
Abstract: The clinical spectrum of hepatitis C is variable and the factors responsible for these divergent outcomes with chronic hepatitis C infection remain unknown. We propose to study a cohort of hemophilic siblings infected with hepatitis C to define the natural history, immunologic, and genetic factors that influence its clinical outcome. Patients with hemophilia have a prevalence rate of hepatitis C as high as 90 percent. The sex-linked pattern of inheritance of hemophilia allows us to identify a cohort of siblings both of who have been infected with hepatitis C. Hemophilic siblings are an attractive population to study because 1) They are all males; 2) Siblings will be relatively close in age; 3) The mode of HCV acquisition is identical; 4) The age at acquisition of hepatitis C is similar 5) The date of acquisition can be confidently estimated upon their factor replacement history; 6) Hemophilic sibs share significant amounts of genetic material. Hemophilic siblings with hepatitis C will undergo a detailed clinical evaluation to stage their liver disease and to identify sibling pairs with clinically and/or histologically discordant levels of disease activity. These siblings pairs will be further studied to define antigen recognition patterns of peripheral CD8 plus CTL and CD4 plus cells and determine their functional significance. Using peripheral blood mononuclear cells, CD8 plus cells will be assayed for CTL activity against three overlapping vaccinia/HCV constructs covering the entire HCV genome followed by fine cloning to identify HCV-specific CTL epitopes. Peripheral CD4 plus cells will be tested for their ability to proliferate to HCV antigens. Using stimulation index, we will quantitate the presence and magnitude of this response. We will also try to identify immunodominant regions targeted by cytotoxic T cells using HLA class I matched hemophilic siblings. Finally, we will identify specific host genes that are preferentially expressed or repressed in patients with delayed progression of their HCV disease. We will quantitate the expression of mRNAs encoding host antiviral defense and immunoregulatory elements in peripheral blood mononuclear cells (PBMCs) and liver tissue from sibling pairs that have discordant chronic hepatitis C using mRNA libraries that will be screened by high density oligonucleotide arrays. The expression levels of these genes (including, but not limited to, interferon alpha, beta, and gamma; IRF-1 and IRF-2; interferon induced protein kinase; the cellular protein activator of PKR (PACT) RNase L; interferon-inducible RNA-specific adenosine deaminase; a ribonuclease specific for inosine- containing RNA; chemokine receptors CCR1, CCR3, CCR5, and their signal transduction elements; 2´-5´-oligoadenylate synthetase; tumor necrosis factor; FAS receptor; signal transduction components of these antiviral pathways, and both type 1 and 2 cytokines) will be correlated with delayed progression and diminished pathogenesis in paired hemophilic siblings
Keywords: cellular immunity, comorbidity, family genetics, hemophilia A, hepatitis C, sibling MHC class I antigen, cytotoxic T lymphocyte, epidemiology, helper T lymphocyte, hepatitis C virus, host organism interaction, immunopathology, immunoregulation, neutrophil, pathologic process clinical research, epitope mapping, human subject, male
Project start date: 1999-09-30
Project end date: 2003-08-31
5R01HL064817-03 (2001): $516718
5R01HL064817-02 (2000): $435668
3R01HL064817-02S1 (2000): $72542
1R01HL064817-01 (1999): $441478
PILOT--ALCOHOL AND HEPATITIS C HOST RESPONSE AND DISEASE ACTIVITY
Michael W Fried, Associate Professor Of Medicine
University Of North Carolina Chapel Hill Office Of Sponsored Research Chapel Hill, Nc 27599
Grant 5P60AA011605-070009 from National Institute On Alcohol Abuse And Alcoholism IRG: ZAA1
Abstract: The clinical spectrum of chronic hepatitis C is variable and the factors responsible for these divergent outcomes remain unknown. Alcohol consumption has been identified as a co-factor in accelerating the progression of liver disease in patients with chronic hepatitis C. Studies of this issue are difficult because there is no animal model of hepatitis C-induced fibrosis. We propose to prospectively study a cohort of patients infected with hepatitis C who also consume alcohol to define the effects of alcohol consumption on hepatic fibrogenesis, oxidant stress, and expression of mediators of inflammation and fibrogenesis in liver tissue and peripheral blood mononuclear cells. The hypothesis to be tested is that alcohol consumption will increase markers of hepatic inflammation, fibrogenesis and oxidant stress, and ultimately reflect an increase in the progression of liver disease. Subjects with concurrent hepatitis C infection on ongoing alcohol use/abuse will undergo a detailed clinical evaluation, including liver biopsy and blood sampling. A control group of non-drinking subjects with chronic hepatitis C will be matched for gender, estimated duration of HCV infection, and mode of HCV acquisition. We will study the effects of alcohol use on hepatic fibrogenesis using standard histologic techniques and novel immunohistochemical markers of stellate cell activation (alpha-smooth muscle actin, collagen II propeptide) in liver biopsy specimens from alcohol consuming and non-drinking patients with chronic hepatitis C. We will also evaluate lipid peroxidation production products using immunohistochemical techniques with antibodies to 4-nonalal and malondealdehyde. In addition, using specimens obtained from these two cohorts, we will identify mRNAs in liver tissue and peripheral blood mononuclear cells encoding host mediators of inflammation and fibrogenesis that are up-regulated in patients with hepatitis C who consume alcohol. This information will provide key information for developing additional hypotheses to be tested in a larger clinical trial.
Keywords: alcoholic beverage consumption, alcoholism /alcohol abuse, ethanol, fibrosis, hepatitis C, liver cirrhosis, biomarker, epidemiology, gene expression, inflammation, lymphocyte, messenger RNA, monocyte, oxidative stress, oxidizing agent, biopsy, human tissue, immunocytochemistry
Hepatitis C Antiviral Resistance In African Americans
Michael W Fried, Associate Professor Of Medicine
University Of North Carolina Chapel Hill Office Of Sponsored Research Chapel Hill, Nc 27599
Grant 5U01DK060327-05 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Abstract: Secondary analyses of large databases derived from clinical trials of various antiviral agents have suggested recently that there may be racial disparities in response to therapy for hepatitis C. Sustained response rates in African American patients appear to be significantly less than in Caucasian patients treated with the same regimens. This proposal will focus on the design of a collaborative multicenter trial that will establish response rates is African Americans to the newest generation of medications for the treatment of chronic hepatitis C and determine if racial differences in response to therapy persist for these newer agents. Our proposal to participate as a Clinical Center for this cooperative study will emphasize the experience, unique attributes, and patient population of the Liver Program at the University of North Carolina at Chapel Hill that will ensure successful completion of this collaborative project. In this clinical trial, well-defined cohorts of African American and Caucasian patients with chronic hepatitis C (all genotype 1) will be treated with combination therapy (pegylated interferon and ribavirin) to determine differences in virological response rates between the two races. The data generated from this trial will be used to investigate baseline clinical, biochemical and virological factors associated with resistance to therapy among African Americans and a matched cohort of Caucasians. We will establish which factors are most predictive of sustained response and how they may differ between racial groups. In addition, we will determine if HCV viral kinetics differ between the cohort of African Americans and Caucasians. In patients who do not respond to therapy, we will evaluate histologic responses by comparing histologic activity in pretreatment and posttreatment liver biopsies. This information may lead to alternative strategies for managing virologic non-responders in the African American population. We will use novel methods to measure adherence to the protocol and evaluate if there are racial differences in adherence and functional health literacy. This study will also serve as a source of clinical data and clinical specimens to be used for basic science investigations into potential mechanisms of antiviral resistance in African Americans with chronic hepatitis C.
Keywords: African American, antiviral agent, combination chemotherapy, drug resistance, hepatitis C, hepatitis C virus, human therapy evaluation, microorganism disease chemotherapy, racial /ethnic difference, caucasian American, chronic disease /disorder, clinical trial, cooperative study, interferon, outcomes research, pharmacokinetics, ribavirin, therapy compliance, virus RNA, biopsy, human subject, patient oriented research
Project start date: 2001-09-01
Project end date: 2007-04-30
5U01DK060327-05 (2005): $105000
5U01DK060327-04 (2004): $175000
5U01DK060327-03 (2003): $350000
Sponsored Links Excellgen http://Excellgen.com
5U01DK060327-02 (2002): $375000
1U01DK060327-01 (2001): $225340
A Phase I/II Randomized, Placebo Controlled Trial Of Silymarin For Hepatitis C
Michael W Fried, Associate Professor Of Medicine
University Of North Carolina Chapel Hill Office Of Sponsored Research Chapel Hill, Nc 27599
Grant 5U01AT003560-02 from National Center For Complementary And Alternative Medicine IRG: ZAT1
Abstract: Major advances have been made over the last decade in the field of antiviral therapy for chronic hepatitis C. Approximately 50% of patients treated with the combination of peginterferon and ribavirin achieve a sustained virological response. Unfortunately, the remainder either fails to respond or must discontinue treatment prematurely due to adverse events. In addition, a significant number of patients with chronic hepatitis C are never offered therapy because they have contraindications to the rigors of treatment with currently available medications. Additional therapeutic options are needed. Herbal products have been used empirically for centuries as alternative medicines to treat a variety of human disorders. Silybum marianum, or silymarin, is primarily used for its purported beneficial effects in disorders of the liver, which include anti-inflammatory, anti-oxidant, and anti-fibrogenic activities. However, there is little evidence from clinical trials to support the use of silymarin as a treatment for diseases of the liver. Several major limitations of prior clinical investigations on the hepatoprotective effects of silymarin include 1) the use of non- standardized silymarin extracts 2) the incomplete understanding of the relationship between silymarin dose and steady-state exposures to the potentially active isomers of silymarin, confounding the evaluation of safety and efficacy; and 3) the use of heterogeneous patient populations and variable endpoints to assess therapeutic response. In this application we will focus on the design of a phase I pharmacokinetic study that will characterize relationships between high silymarin doses and subject exposure to the four isomers of silymarin. The information obtained from the phase I study will allow a rational decision regarding dosages to be used for a phase II study that will then be performed to evaluate the safety and efficacy of silymarin for the treatment on subjects with chronic hepatitis C who were previously treated with conventional therapies. Our application to participate as a Clinical Center for this cooperative study will emphasize the unique attributes and expertise in drug development of the Liver Program and the faculty at the School of Pharmacy at the University of North Carolina at Chapel Hill that will ensure successful completion of this collaborative project.
Project start date: 2006-08-15
Project end date: 2010-07-31
5U01AT003560-02 (2007): $287241
1U01AT003560-01 (2006): $149358
MENTORING JUNIOR FACULTY: HEPATITIS C CLINICAL RESEARCH
Michael W Fried, Professor
University Of North Carolina Chapel Hill, Office Of Sponsored Research, Chapel Hill, Nc 27599
Grant 5K24DK066144-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Clinicians face two major challenges in managing patients with chronic hepatitis C. First, the natural history of chronic hepatitis C remains poorly understood so that predicting the course for an individual patient for whom we are caring remains imprecise. Epidemiologic studies have implicated a number of host factors, such as gender, alcohol consumption, and HIV co-infection, as being associated with rapidly progressive disease. However, the mechanisms by which these interact to alter disease pathogenesis remain unknown. The second challenge is trying to optimize therapy for a diverse population of patients infected with hepatitis C. Although newer therapies for HCV are increasingly effective, there is a large body of evidence to suggest that certain patient populations respond less well to antiviral therapy than others. To date, there have been no prospective studies addressing these issues or the mechanisms by which this may occur. The UNC Liver Diseases Program, under my direction, is currently active in pursuing various studies that focus on these two important themes in hepatitis C. These studies provide the backbone of my mentoring program for junior faculty and fellows who are actively involved in their design, execution, and analysis. For the purposes of this application, I will focus on one ongoing study involving special populations, funded by NIDDK, that investigates antiviral response and resistance in African Americans with chronic hepatitis C (UO1-DK60327- 01, VIRAHEP-C). I will also provide a synopsis of other ongoing studies that form the core of our HCV research program. My immediate career goal is to maintain the trajectory of patient-oriented research at UNC. In the long-term, I would like to direct a multi-disciplinary team of clinical investigators and basic scientists who can work together closely on translational studies of the pathogenesis of chronic viral hepatitis. Finally, my experiences working within the General Clinical Research Center (GCRC) have been very favorable and I would like to become more actively involved in that program. The K-24 award will allow me to attain my goals by relieving me of some of my clinical commitments, thus allowing me to concentrate further on patient-oriented research. It will provide me with additional time to mentor junior faculty and fellows and continue to foster their development within the context of a burgeoning patient-oriented research program
Keywords: 1-Beta-D-ribofuranosyl-1, 2, 4-triazolo-3-carboxamide; 1-Beta-D-ribofuranosyl-1H-1, 2, 4-triazole-3-carboxamide; AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; African American; Afro American; Afroamerican; Air; Alcohol Drinking; Alcohol consumption; Ancillary Study; Anti-Viral Response; Anti-viral Drug Resistance; Anti-viral Drug Resistant; Antiviral Agents; Antiviral Drug Resistance; Antiviral Drug Resistant; Antiviral Drugs; Antiviral Response; Antiviral Therapy; Antiviral resistance; Antiviral resistant; Antivirals; Award; Biochemical; Black Populations; Black or African American; Blood Serum; Caring; Caucasian; Caucasian Race; Caucasians; Caucasoid; Caucasoid Race; Chair; Chairman; Chairperson; Chairwoman; Chronic Hepatitis C; Chronic type C viral hepatitis; Chronic viral hepatitis; Chronic viral hepatitis C; Clinical; Clinical Investigator; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Combined Modality Therapy; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Development; Disease; Disorder; Drug Resistance, Viral; Enrollment; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; EtOH drinking; Face; Faculty; Fostering; Funding; Gender; Gene Products, RNA; Genotype; Goals; HCV; HCV Chronic Infection; HCV infection; HIV; HTLV-III; Hepatic; Hepatic Disorder; Hepatitis C; Hepatitis C Therapy; Hepatitis C virus; Hepatitis C virus infection; Hepatitis C, Chronic; Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted; Hepatitus C; Heterogeneity, Population; High Prevalence; Histology; History; Host Factor; Host Factor Protein; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; IFN; Immune response; Individual; Infection; Integration Host Factors; Interferons; Investigators; Kinetic; Kinetics; LAV-HTLV-III; Liver diseases; Lymphadenopathy-Associated Virus; Measurement; Measures; Mentors; Metabolic Clearance Rate; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; NANBH; NIDDK; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Digestive Diseases and Kidney Disorders; Natural History; North Carolina; Numbers; Occidental; PBMC; PEG-IFN alpha-2A; PEG-Interferon Alfa-2a; PT-NANBH; Parenterally-Transmitted Non-A, Non-B Hepatitis; Participant; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phase; Population; Population Heterogeneity; Position; Positioning Attribute; Principal Investigator; Programs (PT); Programs [Publication Type]; Progressive Disease; Prospective Studies; Protocol; Protocols documentation; Protocols, Treatment; Purpose; RGM; RNA; RNA, Non-Polyadenylated; RTCA; Race; Racial Group; Rate; Recording of previous events; Regimen; Research; Research Design; Research Personnel; Research Specimen; Researchers; Resistance; Ribavirin; Ribonucleic Acid; Ribovirin; Scientist; Serum; Signal Pathway; Site; Special Population; Specimen; Spinal Column; Spine; Stocks, Racial; Study Subject; Study Type; Testing; Time; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tribavirin; United States; Universities; Vertebral column; Viral; Viral Drug Resistance; Viral Genetics; Virus-HIV; Week; Work; alcohol ingestion; alcohol intake; alcohol product use; alcohol use; alcoholic beverage consumption; alcoholic drink intake; anti-viral resistance; anti-viral resistant; backbone; black American; career; clearance rate; clinical data repository; clinical data warehouse; clinical investigation; cohort; combination therapy; combined modality treatment; combined treatment; data repository; design; designing; disease characteristic; disease/disorder; diverse populations; enroll; ethanol consumption; ethanol drinking; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; etoh use; experience; facial; hepatitis non A non B; hepatitis nonA nonB; hepatopathy; heterogeneous population; host response; immunoresponse; improved; liver disorder; member; multimodality therapy; named group; non A non B hepatitis; non A, non B hepatitis; non-A non-B hepatitis; non-A, non-B hepatitis; patient oriented research; patient oriented study; peginterferon alfa-2a; pegylated interferon alfa-2a; polyethylene glycol-interferon alfa-2A; programs; race differences; racial difference; relational database; resistance to anti-viral; resistance to antiviral; resistance to therapy; resistant; resistant to anti-viral; resistant to antiviral; resistant to therapy; response; study design; therapy resistant; translational study; treatment of viral infectious disease; virus genetics; white race
Project start date: 2004-07-01
Project end date: 2010-06-30
Budget start date: 1-JUL-2008
Budget end date: 30-JUN-2010
PFA/PA: PA-98-053
5K24DK066144-05 (2008): $0
5K24DK066144-04 (2007): $139317
5K24DK066144-03 (2006): $139317
5K24DK066144-02 (2005): $139317
1K24DK066144-01 (2004): $139317
MENTORING JUNIOR FACULTY: VIRAL HEPATITIS CLINICAL RESEARCH
Michael W Fried, Professor
University Of North Carolina Chapel Hill, Office Of Sponsored Research, Chapel Hill, Nc 27599
Grant 2K24DK066144-06 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Chronic viral hepatitis is a major global cause of morbidity and mortality. Over the last decade, significant progress has occurred in the development of new treatments for chronic hepatitis C and hepatitis B, although management strategy of these diseases continues to evolve. More than half of patients undergoing treatment with peginterferon and ribavirin for chronic hepatitis C can achieve a sustained virological response. However, numerous patients still fail to achieve permanent viral eradication or are not candidates for initial antiviral therapy due to medical or psychosocial comorbidities which are contraindications to peginterferon and ribavirin therapy. In contrast, treatments for chronic hepatitis B with nucleoside analogues, as examples, are better tolerated, although efficacy is generally measured by prolonged viral suppression, rather than permanent cure. For both these diseases, a better understanding of mechanisms of diminished response to therapy, development of optimized treatment regimens, and/or the identification of alternative or novel medications is of critical importance. The UNC Liver Diseases Program, under the direction of Dr. Michael Fried, is extremely active in pursuing studies that focus on treatment of chronic viral hepatitis. For the purposes of this application, we will discuss an ongoing phase I/II study, funded by NCCAM/NIDDK, that investigates silymarin (milk thistle) as an alternative treatment for patients with chronic hepatitis C who failed to respond to conventional antiviral therapy (U01-AT003560, SyNCH). Furthermore, we will review a new study for chronic hepatitis B, the Hepatitis B Clinical Research Network, funded by NIDDK (U01 DK082867). Finally, we will present a detailed synopsis of an investigator initiated study that examines interferon signaling pathways in peripheral blood mononuclear cells utilizing novel methodologies. These studies provide the backbone of the mentoring program for junior faculty and fellows who are actively involved in their design, implementation, and analysis. As demonstrated within this application, mentees have been integrated into these research activities which have provided them with numerous opportunities in a mentored environment within which to develop research skills and to assert their ownership of individual projects. In this competing renewal application for the K24 Mentoring Award, I will provide detailed information regarding my background in patient-oriented research and the successful clinical research and integrated mentoring program that has been developed directly as a result of this award. I will also demonstrate my continued dedication to clinical research and to a diverse group of talented junior investigators for whom I serve as primary mentor. Finally, we will provide examples of several new research initiatives that will continue to ensure effective mentored research opportunities, as well as a plan for the development of interdisciplinary research teams capable of performing translational research studies
Keywords: 1-Beta-D-ribofuranosyl-1, 2, 4-triazolo-3-carboxamide; 1-Beta-D-ribofuranosyl-1H-1, 2, 4-triazole-3-carboxamide; 18 year old; Adherence; Adherence (attribute); Adverse Experience; Adverse event; Alanine; Alanine, L-Isomer; Alternative Medicine; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Antioxidants; Antiviral Agents; Antiviral Drugs; Antiviral Therapy; Antivirals; Apoptosis; Apoptosis Pathway; Award; Blood Sample; Blood Serum; Blood specimen; Carduus marianus; Cell Death, Programmed; Chronic Hepatitis B; Chronic Hepatitis C; Chronic type C viral hepatitis; Chronic viral hepatitis; Chronic viral hepatitis C; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Unspecified; Comorbidity; Conduct Clinical Trials; Coupled; Data; Dedications; Development; Development Plans; Diaries; Diaries (PT); Diaries [Publication Type]; Disease; Disorder; Dose; Dose-Limiting; Drug Kinetics; Drugs; EC 2; Enrollment; Ensure; Environment; Evaluation; Faculty; Funding; Gene Products, RNA; HBV Chronic Infection; HCV; HCV Chronic Infection; Hepatic; Hepatic Disorder; Hepatitis B; Hepatitis B Infection; Hepatitis B, Chronic; Hepatitis C virus; Hepatitis C, Chronic; Hepatitus C; Human; Human, General; IFN; INFLM; Immune response; Individual; Inflammation; Interdisciplinary Research; Interdisciplinary Study; Interferons; Investigators; Isomerism; L-Alanine; Legalon; Liver diseases; Man (Taxonomy); Man, Modern; Masks; Measures; Medical; Medication; Mentors; Method LOINC Axis 6; Methodology; Milk Thistle; Monitor; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Multidisciplinary Collaboration; Multidisciplinary Research; NCCAM; NIDDK; NIH; National Center for Complementary and Alternative Medicine; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Digestive Diseases and Kidney Disorders; National Institutes of Health; National Institutes of Health (U.S.); Normal Range; Normal Values; Outcome; Ownership; Oxidative Stress; PBMC; PBO; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase; Placebos; Plans, Development; Population; Preparation; Programs (PT); Programs [Publication Type]; Protocols, Treatment; RGM; RNA; RNA, Non-Polyadenylated; RTCA; Randomized; Regimen; Research; Research Activity; Research Personnel; Research Support; Researchers; Ribavirin; Ribonucleic Acid; Ribovirin; Safety; Screening procedure; Serum; Severities; Sham Treatment; Signal Pathway; Silimarin; Silybum marianum; Silymarin; Spinal Column; Spine; Study, Interdisciplinary; Time; Toxic effect; Toxicities; Transferase; Translational Research; Translational Research Enterprise; Translational Science; Treatment Period; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tribavirin; United States National Institutes of Health; Vertebral column; Viral; Viral Hepatitis B; Viral hepatitis; alternative treatment; anti-oxidant; backbone; biomarker; clinical investigation; design; designing; diaries; disease/disorder; dosage; drug/agent; eighteen year old; enroll; experiment; experimental research; experimental study; fibrogenesis; hepatopathy; host response; immunoresponse; improved; intervention development; isomer; liver disorder; novel; nucleoside analog; patient oriented research; patient oriented study; placebo controlled study; placebo controlled trial; primary outcome; programs; psychosocial; public health relevance; randomisation; randomization; randomly assigned; research study; response; screening; screenings; serum hepatitis; sham therapy; silibin; silibinin; silicristin; silidianin; silybin; silychristin; silydianin; skills; success; therapy development; translation research enterprise; treatment days; treatment development; treatment duration; treatment of viral infectious disease
Relevance: In this competing renewal application for the K24 Mentoring Award, I will provide detailed information regarding my background in patient-oriented research and the successful clinical research and integrated mentoring program that has been developed directly as a result of this award. I will also demonstrate my continued dedication to clinical research and to a diverse group of talented junior investigators for whom I serve as primary mentor. Finally, we will provide examples of several new research initiatives that will continue to ensure effective mentored research opportunities, as well as a plan for the development of interdisciplinary research teams capable of performing translational research studies
Project start date: 2004-07-01
Project end date: 2015-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-09-037
2K24DK066144-06 (2010): $162564
Sponsored Links Excellgen http://Excellgen.com
A Phase I/II Randomized, Placebo Controlled Trial Of Silymarin For Hepatitis C
Michael W Fried, Associate Professor Of Medicine
Medicineuniversity Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 3U01AT003560-02S1 from National Center For Complementary & Alternative Medicine IRG: ZAT1
Project start date: 2006-08-15
Project end date: 2010-07-31
3U01AT003560-02S1 (2007): $42515
CHRONIC HEPATITIS C INFECTION IN URBAN AFRICAN AMERICANS
Michael W Fried, Associate Professor Of Medicine
Emory University 1599 Clifton Road, 4th Floor Atlanta, Ga 30322
Grant 1U01AI041424-010004 from National Institute Of Allergy And Infectious Diseases
Keywords: African American, epidemiology, hepatitis C, hepatitis C virus, pathologic process, urban area, caucasian American, cooperative study, racial /ethnic difference, clinical research, human subject