1. By:Samia B PharmD Candidate’14 Viral Hepatitis C and Newer Pharmacologic Therapies

2. Overview: Hepatitis C  Hepatitis is a condition marked by inflammation of the liver secondary to a virus. Hepatitis C is a chronic infection transmitted via blood usually by intravenous means.  Six known genotypes of the hepatitis C virus  Half life of 2-3 hours  Lacks proofreading function  Epidemiology  Most common blood-borne pathogen  Hepatitis C affects 3.2 million people in the United States  Largest risk factor: IV drug use  Risk factors  Most common: IVDU  Diagnosis of HIV  Born to mother with Hep C DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print. Hepatitis C Information for Health Professionals. Centers for Disease Control and Prevention, 03 Mar. 2014. Web.

3. Overview: Hepatitis C  Pathophysiology Image from Heim, Markus H. "25 Years of Interferon-based Treatment of Chronic Hepatitis C: An Epoch Coming to an End." Nature Reviews Immunology 13.7 (2013): 535-42. Print.

4. Overview: Hepatitis C  Clinical Presentation  Weeks 1-2: Asymptomatic  Weeks 3-12: Symptoms such as fatigue, anorexia, weakness, jaundice, abdominal pain, or dark urine can appear in 30% of patients  If infection lasts >6 months: Notable for diagnosis of chronic HCV Symptoms include: persisting fatigue, right upper quadrant pain, nausea, or poor appetite. At chronic stage, necroinflammatory disease progresses  Diagnosis  Testing HCV antibody test If reactive, PCR test required If known exposure within last 6 months, re-testing required if negative antibody test DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print.

5. Therapy: Hepatitis C Treatment goal Eradicate HCV to prevent the development of cirrhosis, cancer Achieve SVR (sustained virologic response-no virus detected after 24 weeks/6 months of therapy) Prior to treatment Quantitative and genotype testing are performed Baseline viral load and infected genotype are determined-serve as prognostic factors throughout therapy Biopsy Grade and stage determined to direct use of therapy Non-pharmacologic therapy Vaccination for Hep A and Hep B recommended Lifestyle changes DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print.

6. Therapy: Hepatitis C Current available therapies: Standard therapy Peg-interferon PLUS Ribavirin PLUS (If genotype 1 HCV) Protease inhibitors boceprevir or telaprevir DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print. GenotypeTherapeutic Regimen Duration of Therapy 1Peg-IFN + ribavirin + boceprevir or telaprevir Variable, but 24- 48 weeks 2,3,4Peg-IFN + ribavirin 24 weeks

7. Therapy: Hepatitis C Pegylated Interferon Comes in two types Achieves sustained virologic response in only 10% of patients if taken as monotherapy-may work alone if acute HCV Dosage form: solution for injection DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print. Pegasys Solution. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014 Peg-Intron Solution. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

8. Therapy: Hepatitis C Pegylated Interferon (continued) Duration Pegasys: Peg-Intron: The treatment duration for patients with genotype 1 and 4 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks. Pegasys Solution. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014 Peg-Intron Solution. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

9. Therapy: Hepatitis C Pegylated Interferon (continued) MOA: works like endogenous interferon that induces innate antiviral response in order to fight infection Side effects: Depression, flu-like symptoms (fatigue, fever, myalgia). Ribavirin Cannot achieve SVR alone but significantly enhances SVR rates when taken with peg-interferon Dosage form: oral tablet, oral capsule, oral solution DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print. Pegasys Solution. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014 Peg-Intron Solution. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014 Ribavirin Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

10. Therapy: Hepatitis C Ribavirin (cont) Dose frequency: Capsule: When taken with peg-interferon alpha-2b (peg-intron) Ribavirin Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

11. Therapy: Hepatitis C Ribavirin (cont) Dose frequency: Tablet: When taken with peg-interferon alpha 2a (Pegasys) Dose administered in 2 divided doses a day Duration: 48 weeks for patients with genotype 1 and 4; 24 weeks for patients with genotypes 2 and 3 MOA: Not fully understood, but thought to affect HCV RNA by increasing mutations to create non-viable genetic material. May also increase body immune response to virus. Side-effects: anxiety, fatigue, fever, headache Ribavirin Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

12. Therapy: Hepatitis C Protease Inhibitors *Approved only for HCV genotype 1 Boceprevir Given 4 weeks after peg-interferon and ribavirin treatment initiation Improved SVR with peg-interferon and ribavirin combo than combo alone (63-66% vs. 38%) Dosage form: oral capsule Dose: 800 mg 3 times daily (every 7 to 9 hours) after 4 weeks of peginterferon alfa and ribavirin treatment. Duration: 24-48 weeks MOA: Acts directly on HCV by inhibiting a serine protease that leads to the production of full-functioning viral proteins Side-effects: Anemia DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print. Boceprevir Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

13. Therapy: Hepatitis C Protease Inhibitors Telaprevir Used in initial 12 weeks of treatment with peg-interferon and ribavirin Improved SVR with peg-interferon and ribavirin combo than combo alone (75% vs. 44%) Dosage form: oral tablet Dose: 750 mg every 8 hours and must be taken with 20 g of fat for adequate absorption. Duration: 24-48 weeks MOA: Acts directly on HCV by inhibiting a serine protease that leads to the production of full-functioning viral proteins Side-effects: Skin rash, Anemia DiPiro, Joseph T. "Viral Hepatitis." Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2014. N. pag. Print. Telaprevir Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

14. Therapy: Hepatitis C Limitations to current standard HCV therapy Patients have to take at least 7 tablets/capsules of oral medication a day + peg-interferon Side-effects can be a major obstacle to patient’s success in therapy due to neutropenia, thrombocytopenia and anemia causing extensive fatigue, weakness, irritability, etc. Efficacy of PI’s low in patients who have infections other than genotype 1 Liang, T. Jake, and Marc G. Ghany. "Current and Future Therapies for Hepatitis C Virus Infection." New England Journal of Medicine 368.20 (2013): 1907-917. Print.

15. Therapy: Hepatitis C New therapies Olysio (simeprevir)-Approved November 2013 Sovaldi (sofosbuvir)-Approved December 2013 Olysio Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014 Solvadi Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

16. Therapy: Hepatitis C Olysio (simeprevir) *Approved for HCV Genotype 1 Dosage form: Oral Capsule Dose & Frequency: 150 mg once daily Replaces protease inhibitors; still used in combination with peg- interferon and ribavirin Duration: 24-48 weeks MOA: Similar to boceprevir and telaprevir-acts directly on HCV by inhibiting virus protease enzyme to inhibit maturation of viral proteins Side-effects: Rash Olysio Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014 "Simeprevir (Olysio) for Chronic Hepatitis C." Medical Letter (6 Jan. 2014): n. pag. Web.

17. Therapy: Hepatitis C Sovaldi (sofosbuvir) *Indicated for the treatment of genotype 1,2,3, or 4 chronic HCV Dosage form: Oral Tablet Dose & Frequency "Sofosbuvir (Sovaldi) for Chronic Hepatitis C." Medical Letter (20 Jan. 2014): n. pag. Print. Solvadi Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

18. Therapy: Hepatitis C Solvadi (sofosbuvir) continued Replaces protease inhibitors; used in combination with peg- interferon and ribavirin but can also be used without interferon MOA: Nucleotide pro-drug that prevents HCV replication by inhibiting RNA polymerase activity Side-effects: Fatigue, headache and weakness-similar side effects as peg-interferon + ribavirin "Sofosbuvir (Sovaldi) for Chronic Hepatitis C." Medical Letter (20 Jan. 2014): n. pag. Print. Solvadi Oral. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; March 2014

19. Therapy: Hepatitis C Efficacy of newer therapies compared to standard therapy Olysio (Simeprevir) "Simeprevir (Olysio) for Chronic Hepatitis C." Medical Letter (6 Jan. 2014): n. pag. Web.

20. Therapy: Hepatitis C Efficacy of newer therapies compared to standard therapy Sovaldi (sofosbuvir) "Sofosbuvir (Sovaldi) for Chronic Hepatitis C." Medical Letter (20 Jan. 2014): n. pag. Print..

21. Therapy: Hepatitis C Limitations to Newer HCV Therapy Cost of drug: Newer therapies Olysio can cost $66,360 for total therapy Sovaldi costs $1,000 per pill, costing total of $84,000 for full treatment of Solvadi alone Older therapies Telaprevir $66,155 Boceprevir $36,506 Limitations of Olysio (Simeprevir) Is not as effective as telaprevir nor boceprevir for NS3 Q80K mutation in genotype 1a Can cause rash and photosensitivity reactions "HIV and ID Observations." HIV and ID Observations. NEJM Journal Watch, n.d. Web "Simeprevir (Olysio) for Chronic Hepatitis C." Medical Letter (6 Jan. 2014): n. pag. Web

22. Misc. Reading material on Hepatitis C and emerging therapies  “Current and Future Therapies for Hepatitis C Virus Infection” (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893124/?report=clas sic)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893124/?report=clas sic  The Medical Letter on Drugs and Therapeutics  Sofosbuvir (Sovaldi) for Chronic Hepatitis C  Simeprevir (Olysio) for Chronic Hepatitis C  News articles  “New hepatitis C drugs must be affordable worldwide, say campaigners-The Guardian (http://www.theguardian.com/society/sarah- boseley-global-health/2014/mar/17/hepatitis-c-pharmaceuticals-industry)  “Prices of new hepatitis C drugs are tough to swallow for insurers”  (http://articles.latimes.com/2014/mar/09/business/la-fi-hepatitis-c-drug- costs-20140310)

23. Questions? Thank you!