1. Updates in the Treatment of Hepatitis C Kelsey Palmer, PharmD PGY2 Ambulatory Care Pharmacy Resident Kaiser Permanente Colorado June 4, 2016

2. Disclosures I have no conflicts of interest or financial sponsorship to disclose

3. Learning Objectives Understand the prevalence and pathophysiology of hepatitis C Compare and contrast both past and current treatments for hepatitis C Review new therapies for hepatitis C, including those for less common genotypes

4. Patient Case MP is a 38 year-old male with hepatitis C. He’s reported no symptoms but was tested based on his former IV drug use. He has not used drugs for nearly 2 years. He is told he has genotype 1. Medications: Citalopram 20 mg/day Lisinopril 5 mg/day Significant past medical history: Depression Hypertension Allergies None

5. Prevalence of Hepatitis C Approximately 3 million individuals in the US are infected with hepatitis C 170 individuals infected worldwide Likely greater based on potential undiagnosed cases Becomes chronic in approximately 75-85% of cases www.cdc.gov

6. Pathophysiology Spherical, enveloped, single-stranded RNA virus Targets hepatocytes Viremia persists in majority of infected individuals Varying degrees of hepatic fibrosis and inflammation Pawlotsky JM. Trends Microbiol. 2004.

7. Acute vs. Chronic Acute Short-term viral infection Some individuals may not experience symptoms Infectious only for small window of time If symptoms do present, typically mild and include fatigue and vomiting Disease resolves without treatment Acute Short-term viral infection Some individuals may not experience symptoms Infectious only for small window of time If symptoms do present, typically mild and include fatigue and vomiting Disease resolves without treatment Chronic Disease does not improve or resolve May lead to long-term problems including liver damage or cancer Chronic Disease does not improve or resolve May lead to long-term problems including liver damage or cancer www.cdc.gov

8. Hepatitis C Genotypes Genotype- classification of the virus based on genetic material May be broken down further into subtypes Genotype 1a, 1b Genotype 2a, 2b, 2c, 2d Genotype 3a, 3b, 3c, 3d, 3e, 3f Genotype 4a 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j Genotype 5a Genotype 6a http://www.hepatitis.va.gov/provider/ reviews/genotypes.asp

9. Hepatitis C Genotypes Genotype 1 is the most common Approximately 75% of cases are genotype 1 (a or b) Approximately 25% have genotypes 2 or 3 Helpful to know genotype for treatment recommendations Duration of therapy differs based on genotype Different areas of the world have different distributions of genotypes http://www.hepatitis.va.gov/provider/reviews/genotypes.asp

10. Symptoms of Hepatitis C Majority of people (70-80%) do not experience symptoms If symptoms do arise, they are generally mild/flu-like: Fatigue Muscle pain Poor appetite Nausea/vomiting Fever Itchy skin Dark urine Jaundice Hepc.liverfoundation.org

11. Who Should be Treated? Recommended for all patients with chronic hepatitis C, excluding those with short life-expectancies from co- morbid conditions Immediate treatment is assigned the highest priority, which includes patients with: Advanced fibrosis Compensated cirrhosis Liver transplant recipients Severe extrahepatic hepatitis C High risk of transmission Hepatitis C Online

12. Treatment Controversy Newer, highly effective oral agents prevent overutilization of healthcare resources May prevent transplant/complications down the road Upwards of 95% cure rate Many of these medications have been dubbed “$1000-a-day pills” Only a small number of patients with hepatitis C go on to develop cirrhosis No way to identify which patients with hepatitis C will progress to severe liver disease Schiff L. Clin Ther. 2015.

13. AgentDoseADRCombo UseOther RibavirinWeight Based 1000mg/day <75kg, 1200mg/day >/=75kg dependent on genotype Severe, not well tolerated 2 black box warnings: hemolytic anemia, birth defects Never as monotherapy Resistance Major drug interactions Peginterferon (PEG-IFN) 180 mcg subq once weekly Dose modifications for leukopenia, thrombocytopenia, depression, increased ALT, renal insufficiency Numerous, frequently problematic Neutropenia, thrombocytopenia, ocular symptoms Only approved in combo with ribavirin with compensated liver disease +/- direct antiretroviral No resistance issues Fewer drug interactions C/I in autoimmune hepatitis, hepatic decomposition in cirrhosis Hepatitis C Online. Ribavirin. Peginterferon.

14. Olysio® (simeprevir) Approved November 2013 Mechanism: NS3/4A protease inhibitor Genotypes: Originally approved for genotype 1 in combination with PEG-INF and ribavirin November 2014- approved in combination with sofosbuvir for patients with genotype 1 Never used as monotherapy May cause photosensitivity reaction Resistance can be a significant problem Simeprevir package insert

15. Sovaldi® (sofosbuvir) Approved December 2013 Mechanism: nucleotide analog NS5B polymerase inhibitor Genotypes: Approved for genotypes 1 and 4 for treatment-naïve adults in combo with PEG-IFN and ribavirin 1 st approved interferon-free treatment regimen for HCV genotypes 2 and 3 Well-tolerated High genetic barrier to resistance Noell BC. Drug Des Devel Ther. 2015.

16. Harvoni® (ledipasvir/sofosbuvir) Approved October 2014 Mechanism: Ledipasvir- NS5A inhibitor Sofosbuvir- nucleotide analog NS5B polymerase inhibitor Genotypes: Originally approved for genotype 1 (treatment-naïve and experienced) November 2015- expanded for use in genotype 4,5,6 and for co-infection with HIV February 2016- expanded for use in genotype 1 who are liver transplant recipients Once-daily, uncomplicated regimen (favorable for adherence) Harvoni package insert.

17. Viekira Pak® (ombitasvir, paritaprevir, ritonavir, and dasabuvir) Approved December 2014 Mechanism: Ombitasvir- NS5A inhibitor Paritaprevir- NS3/4A protease inhibitor Ritonavir- CYP3A4 inhibitor Dasabuvir- NS5B polymerase inhibitor May be used with or without ribavirin Recommended to be used with ribavirin except for 1b without cirrhosis Genotypes: Approved for genotype 1 a and b, with or without cirrhosis Viekira Pak package insert.

18. Daklinza® (daclatasvir) Approved July 2015 Mechanism: NS5A inhibitor Genotypes: Indicated for genotype 3 (in combination) Feb 2016- expanded use (in combination) with or without ribavirin for genotypes 1 and 3 Also included co-infection, decompensated cirrhosis, or following liver transplantation Indicated for use with sofosbuvir Recommended duration of therapy is 12 weeks, although optimal duration remains unknown Daklinza package insert.

19. Zepatier® (elbasvir/grazoprevir) Approved January 2016 Mechanism: Elbasvir- NS5A inhibitor Grazoprevir- NS3/4A protease inhibitor Genotypes: Approved for genotypes 1 and 4 Recommended to test for polymorphisms to determine duration and addition of ribavirin Distinct from earlier generation protease inhibitors Activity against some major resistance-associated variants Zepatier package insert.

20. Selection of Treatment Regimen Consider the following: Genotype History of prior treatment (naïve vs. experienced) Stage of fibrosis Adverse effect profile Drug interactions Duration of therapy Cost

21. GenotypeRegimens- Treatment Naïve Regimens- Treatment Experienced Genotype 1 Ledipasvir-sofosbuvir Elbasvir-grazoprevir Ombitasvir-paritaprevir- ritonavir + dasabuvir ( +/- wt based ribavirin) Simeprivir + sofosbuvir Daclatasvir + sofosbuvir Prior PEG-IFN and ribavirin failure Ledipasvir-sofosbuvir Elbasvir-grazoprevir Ombitasvir-paritaprevir- ritonavir + dasabuvir Simeprevir + sofosbuvir Daclatasvir + sofosbuvir Prior protease inhibitor failure Ledipasvir-sofosbuvir Daclatasvir + sofosbuvir +/- wt based ribavirin

22. GenotypeWith cirrhosisWithout cirrhosis Genotype 2Sofosbuvir + wt based ribavirin (12 weeks) Daclatasvir + sofosbuvir if contraindication to ribavirin (12 weeks) Sofosbuvir + wt based ribavirin (16 weeks) Daclatasvir + sofosbuvir if contraindication to ribavirin (24 weeks) Genotype 3Daclatasvir + sofosbuvir + wt based ribavirin (24 weeks) Other options less preferable as they are longer duration, include interferon, more expensive, not well studied Daclatasvir + sofosbuvir (12 weeks)

23. GenotypeRecommended Therapies Genotype 4Ledipasvir-sofosbuvir (12 weeks, regardless of cirrhosis or previous failure) Elbasvir-grazoprevir (+ wt based ribavirin if treatment experienced) Ombitasvir-paritaprevir-ritonavir + ribavirin Sofosbuvir + ribavirin Genotype 5Ledipasvir-sofosbuvir (12 weeks) Sofosbuvir + PEG-IFN + ribavirin (12 weeks) Genotype 6Ledipasvir-sofosbuvir (12 weeks) Sofosbuvir + PEG-IFN + ribavirin (12 weeks)

24. Back to MP…. What additional information do you want to know? Drinks alcohol, but no cirrhosis Minimal liver fibrosis Has not previously tried/failed other therapies Treatment is not cost-prohibitive for him Does not have renal disease His viral load is >6 million international units/mL

25. Back to MP… What treatment option would you chose for MP? A) Daclatasvir + sofosbuvir + wt based ribavirin GREEN B) Ledipasvir-sofosbuvir PINK C) Simeprevir PURPLE D) Ombitasvir-paritaprevir-ritonavir plus dasabuvir YELLOW

26. Back to MP… You decide to use ledipasvir-sofosbuvir to treat MP Do you want to use in combination with ribavirin? A) Yes GREEN B) No PINK How long should he be treated for? A) 8 weeks GREEN B) 12 weeks PINK C) 24 weeks PURPLE D) 48 weeks YELLOW

27. Questions? Contact: Kelsey Palmer, PharmD PGY2 Ambulatory Care Pharmacy Resident Kelsey.E.Palmer@kp.org