1. New Treatments of Hepatitis C
PHM Fall 2015
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
New Treatments of Hepatitis C
PHM 142
Fall 2015
Presented by: Chantel Asamoah ( )
Sarah He ( )
Liborio Borsellino ( )
Theresia Wibowo ( )

2. What is Hepatitis C?
Hepatitis C is a disease caused by a virus that infects hepatocytes. It can lead to liver scarring, cirrhosis (nodules), liver failure, and liver cancer.1
Hepatitis C Virus (HCV) is a positive strand RNA virus encoding for a polyprotein that undergoes a polypeptide cleavage to 10 polypeptides, each with different functions1
Structural proteins: consist of 2 envelope proteins E1 & E2.1 Both envelope proteins target host antibody response.1
Non-structural proteins: NS2, NS3, NS4A, NS4B, NS5A, NS5B1 Form a complex with viral RNA to initiate viral replication.1

3. The Life Cycle of Hepatitis C

4. What does it do to the body?
1) Virus goes to liver and starts to reproduce using host machinery
2) Sends immune cells to attack the virus and the liver cells infected with the virus1
3) These liver cells become inflamed and then die1
Causes scar tissue on the liver1
Untreated HCV can lead to cirrhosis1

5. Transmission of HCV Transmitted through the blood1
Ex. sex, sharing toothbrushes, sharing razors, birth

6. Older Treatments of Hepatitis C: Interferon & Ribavirin
Interferon alpha is an inhibitor of HCV replication that induces specific host genes with antiviral functions1
Ribavirin acts in synergy with interferon alpha; boosts efficacy from 10% to 50%1
Older treatment options are interferon- ribavirin drug regimens that have a % cure rate depending on the HCV genotype.
Many patients can’t tolerate interferon due to side effects and comorbidities, while ribavirin is teratogenic1
Used to treat Hepatitis C for 20 years
Ribavirin

7. Older Treatments of Hepatitis C: Interferon & Ribavirin
Process of how (endogenous) interferon works:
Virus enters cell and use host machinery to reproduce1
Interferon genes are turned on1
Produced and released by dying cell1
Binds to the receptor on the cell membrane which turns on genes for antiviral proteins1
Antiviral proteins block viral production1
Interferon alpha (exogenous)
This drug induces host-genes that have anti viral function1
Interferon side effects
Cytopenia, depression, autoimmunity and rashes1
Ribavirin
Ribavirin competes with guanosine in the formation of viral mRNA cap structure1
Interferes with enzymes responsible for functional methylation which is crucial for the virus1

8. Protease Inhibitors Protease inhibitors2 Boceprevir Telaprevir
Simeprevir
For genotype 1 infection
Most common genotype worldwide3
Least responsive to interferon and ribavirin based therapy so these treatments are used in conjunction with protease inhibitors3
Direct-acting antivirals (DAA)- inhibit viral replication by targeting specific steps in the HCV life cycle 3

9. Boceprevir
Protease inhibitor of the hepatitis C virus non-structural protein serine protease2
Covalently and reversibly binds to NS3/4A protease active site through alpha-ketoamide functional group2
Prevents the polyprotein precursors from maturing into mature forms of NS4A, NS4B, NS5A, NS5B2

10. Sofosbuvir: A Nucleotide Analog
Brand name: Sovaldi4
Works 90% of the time on HCV genotype 2, 3, 44
First interferon free HCV treatment5
Sofosbuvir is a prodrug that is metabolized to its active form 2'-deoxy- 2'-α-fluoro-β-C-methyluridine-5'- triphosphate (GS )4
GS is a uridine analog triphosphate5

11. Sofosbuvir: Mechanism of Action
Uridine triphosphate GS
The NS5B protein made by the virus is a RNA polymerase5
GS differs from uridine triphosphate because of the fluoro and methyl group on the 2’ carbon4
GS competes with uridine triphosphate in the body for incorporation into the new RNA strand being made4
This increased electronegativity of the flouro group causes irreversible binding and stops RNA replication4

12. NS5A Inhibitors
DAA that directly inhibits NS5A protein, which is important in:
Regulating viral RNA replication6
Viral assembly6
Inhibition of host cell apoptosis6
In the presence of NS5A inhibitor:
Inhibition of viral replication and virion assembly6
Inhibition of secretion from infected cell6
Decline in HCV RNA levels
Redistribution of NS5A from ER to lipid droplet6

13. NS5A Inhibitor Mechanism
Two different pathways in RNA replication:
Inhibition of NSA hyperphosphorylation7
Phosphorylation of NS5A required for viral production7
Regulation of phosphorylation vs. hyperphosphorylation required for viral function7
Alteration the subcellular localization of NS5A, causing faulty viral assembly8

14. Daclatasvir (Daklinza)
Targets HCV genotype 36
Combination with sofosbuvir
Ledipasvir
Combination with sofosbuvir (Harvoni) and simepravir WITHOUT interferon or ribavirin!6
Minor side effects6
Development of new treatments can potentially treat HCV without adverse effects of ribavirin and interferon6

16. Summary Older treatment: Interferon & Ribavirin
Interferon side effects: Cytopenia, depression, autoimmunity and rashes
3 Examples of New Treatment
Protease inhibitors
Broceprevir, Telaprevir, Simeprevir
Inhibitors of genotype 1 infection
Protease inhibitors used in conjunction with interferon and ribavirin
Sofosbuvir: A Nucleotide Analog
Sofosbuvir is a prodrug that is metabolized to GS , a competitor of uridine triphosphate
The flouro group on GS causes irreversible binding to NS5B and stops RNA replication
NS5A inhibitors:
Daclatasvir (Daklinza)
Combination of ledipasvir & sofosbuvir (Harvoni)
Combination of ledipasvir & simepravir
Act WITHOUT interferon & ribavirin

17. References
T. Jake Liang, M.D., et al.(2013). “Current and Future Therapies for Hepatitis C Virus Infection.” The New England Journal of Medicine. Web. 6 Nov
Garnock-Jones, Karly. "Boceprevir." Drugs (2012): ProQuest. 9 Nov
Perry, Caroline M. "Telaprevir." Drugs 72.5 (2012): ProQuest. 9 Nov
Cada, Dennis J., Jasen Cong, and Danial E. Baker. “Sofosbuvir.” Hospital Pharmacy (2014): 46
Stedman, Catherine. “Sofosbuvir, a NS5B Polymerase Inhibitor in the Treatment of Hepatitis C: A Review of Its Clinical Potential.” Therapeutic Advances in Gastroenterology 7.3 (2014): 131–140. PMC. Web. 10 Nov. 2015
Jean-Michel Pawlotsky, NS5A inhibitors in the treatment of hepatitis C, Journal of Hepatology, Volume 59, Issue 2, August 2013, Pages , ISSN ,
Ying Huang, Kirk Staschke, Raffaele De Francesco, Seng-Lai Tan, Phosphorylation of hepatitis C virus NS5A nonstructural protein: A new paradigm for phosphorylation-dependent viral RNA replication?, Virology, Volume 364, Issue 1, 20 July 2007, Pages 1-9, ISSN ,
P. Targett-Adams, E.J. Graham, J. Middleton, A. Palmer, S.M. Shaw, H. Lavender, et al.Small molecules targeting hepatitis C virus-encoded NS5A cause subcellular redistribution of their target: insights into compound modes of action. J Virol, 85 (2011), pp. 6353–6368