Combination therapies for chronic HBV, liver disease and cancer

Summary

Principal Investigator: Mark A Feitelson
Affiliation: Temple University
Country: USA
Abstract: There are an estimated 350 million people worldwide who are chronically infected with hepatitis B virus (HBV) and are at high risk for the development of hepatitis, cirrhosis (end stage liver disease) and hepatocellular carcinoma (HCC). Hepatitis and cirrhosis are associated with prolonged morbidity, and HCC, which appears in more than 250,000 people each year, is rapidly fatal. Given that the major risk factors for HCC are the HBV carrier state (defined as the persistence of virus or virus antigens in blood for more than 6 months) and chronic liver disease (CLD) (hepatitis and cirrhosis), the most direct way to reduce risk factors for HCC is to target the virus and/or corresponding immunity. Accordingly, the FDA has now approved interferon 1, pegylated interferon 1, lamivudine, adefovir dipivoxal, entecavir, and telbivudine. Additional drugs, such as emtricitabine, clevudine, and tenofovir, will probably be approved soon. Although these are potent drugs, they are limited by low rates of sustained response, side effects, and the emergence of drug resistance. Hence, the objective of this proposal is to devise combination therapies, following the model of HIV combination therapy development, to successfully treat long term HBV infection. To do so, the lab will assess the pharmacokinetics (PK), antiviral efficacy and toxicity of drug combinations in primary human hepatocytes and in HepG2 cells replicating wild type or selected mutants of HBV (aim 1). Favorable combinations will then be assessed in vivo in nude mouse injected with HepAD38 cells (AD38 cells replicate wild type HBV, which accumulates in the blood of these mice) in order to get a sense of what combinations and concentrations of drugs are most effective in reducing virus titer, for assessing how long virus DNA levels remain suppressed during and after treatment, and whether different combinations have a favorable PK profile in vivo (aim 2). The best combinations will then be evaluated for long term antiviral efficacy in HBV transgenic SCID mice, which stably replicate wild type HBV and develop CLD (aim 3). This work will develop combination therapies that will demonstrate a sustained antiviral effect against HBV, against HBV in HIV co-infected patients, in chronically infected alcoholics, as well as prolonged suppression of CLD. Elimination of CLD will reduce the risk of chronic HBV carriers of developing HCC. This will contribute centrally to the design of future clinical trials that will be suitable for long term treatment of chronic infections without significant side effects or the frequent development of drug resistance that limit present day therapeutics against HBV. PUBLIC HEALTH RELEVANCE There are more than 350 million people worldwide chronically infected with hepatitis B virus (HBV) and who are at risk for the development of hepatitis (inflammation of the liver), cirrhosis, and liver cancer. Millions of people each year die from liver cirrhosis. Liver cancer is among the top five most prevalent tumor types worldwide, with an estimated 1 million deaths each year. Present treatments for chronic hepatitis B use single drugs that are expensive, have side effects, and select for drug resistant viruses. Hence, new therapeutic options to treat long term virus infection and associated diseases are urgently needed. The proposed work will develop combination therapies with sustained antiviral effect against HBV and associated chronic liver disease, against HBV in HIV co-infected patients, and against HBV among chronic alcoholics. Prevention and/or elimination of chronic liver disease will reduce the risk of HBV carriers developing cirrhosis and liver cancer, thereby contributing centrally to improving public health.
Funding Period: ----------------2008 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Evaluation of single and combination therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust mouse model supporting high levels of hepatitis B virus replication
    Raymond F Schinazi
    Department of Pediatrics, Emory University School of Medicine, Decatur, GA, USA
    Antimicrob Agents Chemother 56:6186-91. 2012
  2. pmc Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein
    Alla Arzumanyan
    Department of Biology, Temple University, Philadelphia, Pennsylvania 19122, USA
    Cancer Res 72:5912-20. 2012
  3. doi Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma
    Alla Arzumanyan
    Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, USA
    Nat Rev Cancer 13:123-35. 2013
  4. pmc Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly
    Guoyi Wu
    Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
    Antimicrob Agents Chemother 57:5344-54. 2013
  5. pmc Human viral oncogenesis: a cancer hallmarks analysis
    Enrique A Mesri
    Viral Oncology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA AIDS Malignancies Scientific Working Group, Miami Center for AIDS Research, Department and Graduate Program in Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA Electronic address
    Cell Host Microbe 15:266-82. 2014
  6. pmc HCV drug discovery aimed at viral eradication
    R F Schinazi
    Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Veterans Affairs Medical Center Emory University School of Medicine, Atlanta, GA, USA
    J Viral Hepat 17:77-90. 2010
  7. pmc Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages
    Edward M Kennedy
    Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA
    J Biol Chem 285:39380-91. 2010
  8. doi Advances in nucleoside monophosphate prodrugs as anti-HCV agents
    Drew R Bobeck
    RFS Pharma LLC, Tucker, GA, USA
    Antivir Ther 15:935-50. 2010

Scientific Experts

  • R F Schinazi
  • Baek Kim
  • Alla Arzumanyan
  • Mark A Feitelson
  • Enrique A Mesri
  • Guoyi Wu
  • Marcia M Clayton
  • Drew R Bobeck
  • Edward M Kennedy
  • Karl Munger
  • Helena M G P V Reis
  • Bo Liu
  • Yingjun Zhang
  • Faxhou Zhang
  • Qingyun Ren
  • Zhaohe Wang
  • Siegfried Goldmann
  • Jing Li
  • Guanhua Xie
  • Vaishnavi Sambandam
  • Steve S Choi
  • Dae Yeul Yu
  • Anna Mae Diehl
  • Christina Gavegnano
  • Amanda Lucas
  • Rebecca Slater
  • Steven J Coats
  • Emilie Fromentin
  • Laura Nguyen

Detail Information

Publications9

  1. pmc Evaluation of single and combination therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust mouse model supporting high levels of hepatitis B virus replication
    Raymond F Schinazi
    Department of Pediatrics, Emory University School of Medicine, Decatur, GA, USA
    Antimicrob Agents Chemother 56:6186-91. 2012
    ..TDF-(-)-FTC combination therapy provides more effective HBV suppression than therapy with each drug alone...
  2. pmc Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein
    Alla Arzumanyan
    Department of Biology, Temple University, Philadelphia, Pennsylvania 19122, USA
    Cancer Res 72:5912-20. 2012
    ..This work could be central to designing specific treatments that target early development and progression of HBx-mediated HCC...
  3. doi Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma
    Alla Arzumanyan
    Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, USA
    Nat Rev Cancer 13:123-35. 2013
    ..This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC...
  4. pmc Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly
    Guoyi Wu
    Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
    Antimicrob Agents Chemother 57:5344-54. 2013
    ..Thus, GLS4 was as potent as the prototype, BAY 41-4109, and was superior to lamivudine, in that there was little virus relapse after the end of treatment and no indication of toxicity. ..
  5. pmc Human viral oncogenesis: a cancer hallmarks analysis
    Enrique A Mesri
    Viral Oncology Program, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA AIDS Malignancies Scientific Working Group, Miami Center for AIDS Research, Department and Graduate Program in Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA Electronic address
    Cell Host Microbe 15:266-82. 2014
    ....
  6. pmc HCV drug discovery aimed at viral eradication
    R F Schinazi
    Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Veterans Affairs Medical Center Emory University School of Medicine, Atlanta, GA, USA
    J Viral Hepat 17:77-90. 2010
    ....
  7. pmc Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages
    Edward M Kennedy
    Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA
    J Biol Chem 285:39380-91. 2010
    ..This study reveals that the biochemical landscape of HIV-1 replication in macrophages is unique and that ribonucleoside chain terminators may be a new class of anti-HIV-1 agents specifically targeting viral macrophage infection...
  8. doi Advances in nucleoside monophosphate prodrugs as anti-HCV agents
    Drew R Bobeck
    RFS Pharma LLC, Tucker, GA, USA
    Antivir Ther 15:935-50. 2010
    ..This review discusses recent advances in monophosphate prodrug approaches to improve oral absorption, stability and pharmacokinetic profile, including their advantages and potential pitfalls...