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Presented By: David Zugell 4/4/2009 Southern Methodist University

Hepatitis C Virus. Presented By: David Zugell 4/4/2009 Southern Methodist University. Outline. General overview Causes Inside the Body Complications Treatment Medication Vaccine Conclusion. OverVeiw. Only infects humans and chimpanzees

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Presented By: David Zugell 4/4/2009 Southern Methodist University

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  1. Hepatitis C Virus Presented By: David Zugell 4/4/2009 Southern Methodist University

  2. Outline • General overview • Causes • Inside the Body • Complications • Treatment • Medication • Vaccine • Conclusion

  3. OverVeiw • Only infects humans and chimpanzees • This is a virus that mainly affects the Liver • Asymptomatic • Only lives for about 16 hours outside the human body.

  4. About the Virus • Ribonucleic acid (RNA) • 10,000 units called nucleotides • family Flaviviridae and genus hepacivirus • 40 to 60 nanometers in diameter • six major genetic types (genotypes) and many more subtypes • genotype 1 (1a and 1b), which accounts for 80% of hepatitis C virus cases in the U.S. • patients infected with genotypes 2 or 3 are much more likely to respond to interferon therapy. In contrast, patients infected with genotype 1 (particularly 1b) or genotype 4 do not respond very well to interferon therapy

  5. Prevalence • More than 4 million Americans (1.3% of the U.S. population) and 170 million individuals in the world (3% worldwide)

  6. Prevalence

  7. Prevalence

  8. Prevalence

  9. Transmission

  10. Transmission • Drug use • Through injection • Sharing needles, spoons, cotton, water, etc. • Also nasal inhalation • Cocaine and Crystal Methamphetamine

  11. Transmission • Blood products • Organ transplants • Blood transfusion • prior to implementation of HCV screening • In the U.S., this would refer to procedures prior to 1992

  12. Transmission • Sexual activity • Rarely transmitted in this fashion • Spouses are encourage to use a condom • Food • Rarely transmitted in this fashion • Even during kissing it is hard to obtain the virus. (unless and open sore is present) • Hygiene • It is also not recommended that you share toothbrushes.

  13. Diagnosis • Early signs: • fatigue, weight, retention of urine, muscular aches, poor appetite, • Hepatitis C is most readily diagnosed when serum aminotransferases are elevated and anti-HCV is present in serum. The diagnosis is confirmed by the finding of HCV RNA in serum

  14. Early Entry • apolipoprotein complexes • low-density lipoprotein receptor (LDL-R) • glycosaminoglycans (GAGs) • On Cell Surface • CD81 • scavenger receptor class B type 1 (SR-B1) development • CLDN1

  15. Progression

  16. Liver Damage • The HCV accumulates in the liver. • Caused by human immune systems response to the HCV • includes cytotoxic (injurious to cells) • lymphocytes • specific inflammatory messengers (cytokines).

  17. Liver Damage • HCV causes the following changes in liver tissue: • Necrosis and inflammation at the edge of the portal areas, so-called “piecemeal necrosis” or “interface hepatitis” • Necrosis of hepatocytes and focal inflammation in the liver parenchyma • Inflammatory cells in the portal areas (“portal inflammation”)

  18. Liver Damage • CYP2E1, an enzyme involved in the breakdown of alcohol in the live • breaks down potentially toxic foreign substances (i.e., xenobiotics), including alcohol. • Enhanced activity results in the increased generation of acetaldehyde from alcohol, free radicals (e.g., superoxide [O2.] and hydroxyl [OH.]) that can cause liver injury by promoting excessive breakdown of fat molecules (i.e., lipid peroxidation). • free radicals most likely potentiate the HCV-associated oxidative stress and the resulting liver damage

  19. Ribavirin • By itself, ribavirin has little effect on HCV • Used in como with interferon • Rabavirin tab 200mg • 2 times a day 2 pills each time • Side effects • anemia, fatigue, insommia depression, hair loss.  nausesa & loss of appetite

  20. Combination Therapy • improvements in serum ALT levels & detectable HCV RNA in up to 70 percent of patients • 48-week course • Only 55% remain HCV Free

  21. Treatment

  22. Inhibitors of HCV Polymerase

  23. Polymerase Inhibitors • protein NS5B is cleaved from the HCV polyprotein by the NS3 serine protease, and functions as a RNA-dependent RNA polymerase • nucleoside polymerase inhibitors • inhibit the active site causing chain termination (for example, valopicitabine (NM-283), MK-0608, R1626, PSI-6130 and its prodrug R7128), • non-nucleoside polymerase inhibitors • allosteric inhibition resulting in a conformational change of the protein (for example, BILB 1941 and HCV-796)

  24. Valopicitabine (NM-283)

  25. Non-nucleoside Inhibitors

  26. Valopicitabine (NM-283)

  27. Non-nucleoside Inhibitors

  28. NNI Active Sites

  29. Mutations

  30. Drug Development • Company Drug Development Phase • Vertex Telaprevir (VX-950) Protease Inhibitor Phase 3 • Vertex VX-500 protease inhibitor Phase 1 • Vertex VX-813 2nd gen protease inhibitor Pre Clinical • Schering Boceprevir (SCH503034) Protease inhibitor Phase 3 • Intercell Novartis IC41 Therapeutic Vacccine Phase 2 • Chiron / CSL Therapeutic Vaccine CSL123 Phase 2 • Roche R1626 Polymerase inhibitor Phase 2 • Intermune / Roche Protease inhibitor ITMN-191 R7227 Phase 1 • Roche / Pharmasset R7128 nucleoside polymerase inhibitor Phase 1 • Roche / Medivir HCV polymerase inhibitor R & D • Medivir / Tibotec TMC435 Protease inhibitor Phase 2 • Medivir / Tibotec polymerase inhibitor R & D • Pfizer PF-868554 Non-Nuc Polymerase inhibitor Phase 2 • Benitec / Tacere Bio / Pfizer RNA interference TT033 Pre Clinical • ViroChemPharma VCH-759 Non nuc Polymerase inhib Phase 2 • ViroChemPharma Polymerase inhib Pre Clinical • ViroChemPharma Polymerase inhib R & D • Globeimmune GI 5005 Therapeutic Vaccine Phase 2

  31. Telaprevir (VX-950) • Telaprevir, also known as VX-950 is an oral Protease Inhibitor (NS3-4A). It is being developed by Vertex Pharmaceuticals for the treatment of hepatitis C virus. • Patients with Genotype 1 Hepatitis C support potential to shorten treatment duration in treatment-naïve, genotype 1 HCV patients.

  32. IC41 • IC41 is a therapeutic peptide vaccine. It is being developed by Intercell AG for the treatment of hepatitis C. The vaccine consists of five synthetic peptides (IPEP83, 84, 87, 89,1426) harboring HCV CD4 and CD8 T-cell epitopes and the synthetic adjuvant poly-L-arginine.

  33. Non-Traditional Treatment • Milk Thistle • Flowering plant from Europe • Said to repair and prevent liver damage. • Alpha Lipoic • antioxidant • Used in body to create energy

  34. Conclusion • Millions of people are infected. • Causes damage to the liver. • Several different genotypes (1 most common in U.S.) • Several treatment options • Hard to transfer the virus • A vaccine is in Phase 2 trails

  35. References • http://www.vizier-europe.org/IMG/pdf/RDeFrancesco_VIZIER_2007.pdf • http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/ • http://www.nature.com/nrd/journal/v6/n12/full/nrd2411.html • http://www.hcvdrugs.com/forum/list.php?17 • http://journals.elsevierhealth.com/periodicals/ygast/article/S0016-5085(08)02048-9/abstract • http://en.wikipedia.org/wiki/Hepatitis_C • www.abbottmolecular.com/HepatitisCDemographic... • http://en.wikipedia.org/wiki/Milk_thistle

  36. Questions?

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