An Update on the Treatment of Hepatitis C

An Update on the Treatment of Hepatitis C Audrey Broyer, Pharm D, CGP Clinical Pharm acy Specialist Manchester VA Medical Center

Disclosure Statement I have no relevant financial relationships that would bias or compromise the presentation of these materials. Therapies not fully evaluated or approved by the FDA will be mentioned: Off-label recommendations supported by guidelines but not FDA approved

Objectives Discuss the pathophysiology and diagnosis of Hepatitis C virus Identify patients with chronic Hepatitis C virus that are appropriate for treatment Chose appropriate medication and duration of treatment for patient with Hepatitis C virus based on genotype, treatment history and other factors Provide education including potential side effects and drug interactions that are commonly encountered during Hepatitis C virus treatment

Chronic Hepatitis C Virus (HCV) 2.7 million people in the US Birth Cohort: higher risk 1945-1965 Other risk factors Injection drug users Received clotting factor concentrates prior to 1987 Received blood transfusion or transplant prior to July 1992 Chronic hemodialysis People with HIV Transmission Injection drug users (#1) 30% of current users 18-30 years old are infected, 70-90% of former users are infected Donated blood or blood products or organs (no longer common) Needlesticks Birth to HCV infected mother Sexual transmission is rare 15-25% of people clear the virus spontaneously Hepatitis C FAQs for Health Professionals. (Oct 14, 2015).

HCV Testing CDC. Testing for HCV infections. 2103

HCV Genotypes Messina JP, Humphreys I, Flaxman A, et al. 2015.

Treatment Goal of treatment to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure.. Who to treat recommend treatment for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Treatment regimen varies based on patient characteristics Genotype Liver health (cirrhotic or non-cirrhotic) Previous treatment Viral load AASLD/IDSA/IAS USA. Treatment Guidelines. 2015.

Hepatitis C Medications 1980s Hepatitis C virus identified 1991 - IntronA (interferon alfa 2b) approved 1998 - Rebetron (interferon alfa 2b + ribavirin) approved, regimen of interferon 3x week + ribavirin 800-1200mg/day for 24-48 weeks 2001 pegylated interferon was approved 2011 first direct acting antivirals (DAA), Victrelis (boceprevir) and Incivek (telaprevir) approved in combination with PEG/RBV 2013 (Nov) Olysio (simeprevir) approved in combination with PEG/RBV 2013 (Dec) Sovaldi (sofosbuvir) approved in combination with PEG/RBV or RBV (first interferon free regimen) 2014 (Nov) Harvoni (ledipasvir/sofosbuvir) approved 2014 (Dec) Viekira Pak (ombitasvir/paritaprevir/ritonavir + dasabuvir) approved 2015 (July) - Technivie (ombitasvir/paritaprevir/ritonavir) and Daklinza (daclatasvir) approved Mandal A. Hepatitis C History. Updated April 26, 2013. Advances in Medications to Treat Hepatitis C. Updated September 2015.

Hepatitis C Online: Peginterferon alpha-2a Drug Summary. 2015. Hepatitis C Online: Peginterferon alpha-2b Drug Summary. 2015. Interferon Alpha Pegasys and PegIntron Mechanism of action not well understood Boosts immune response against hepatitis C virus Pegylated interferon has increased absorption and a longer half life Dosing Pegasys 180mcg subcutaneously weekly PegIntron 1.5mcg/kg subcutaneously weekly Dose adjustment for thrombocytopenia or neutropenia Adverse Drug Reactions - Flu-like symptoms, fatigue, depression, glucose dysregulation and thyroid dysfunction

Ribavirin Rebetrol, Copegus, Ribasphere Available in 200mg tablets, 200mg capsules, 40mg/mL oral solution Purine nucleoside analog mechanism of action against HCV is not understood Increases SVR rates Weight based dosing < 75kg: 1000mg per day 75kg: 1200mg per day Common Adverse Reactions hemolytic anemia, birth defects, rash, fatigue Hepatitis C Online: Ribavirin Drug Summary. 2015

Direct Acting Antiviral Agents Lam BP, Jeffers T, Younoszai Z, et al. 2015.

Simeprevir (Olysio ) NS3/4A inhibitor Approved for Genotype 1 & 4 No longer recommended for genotype 4 Treatment of genotype 1 (with sofosbuvir) Dosing: 150mg once daily with food No adjustment for renal or hepatic impairment Screen patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism Olysio [package insert]. Titusville, NJ: Jansen Therapeutics. 2015.

Simeprevir (Olysio ) Precautions Not recommended in moderate-severe hepatic impairment (Child-Pugh B or C) Hepatic decompensation and failure have been reported Serious symptomatic bradycardia when administered with amiodarone Photosensitivity reactions Rash usually mild-moderate but can progress to severe Contains a sulfonamide moiety Adverse Reactions (from pooled Phase 3 trials) Simeprevir + Sofosbuvir Fatigue (25%), headache (21%), nausea (21%), insomnia (14%), pruritus (11%), rash (11%), photosensitivity (7%) Olysio [package insert]. Titusville, NJ: Jansen Therapeutics. 2015.

Simeprevir Drug Interactions Substrate and mild inhibitor of CYP3A, P-glycoprotein (P-gp), and OATP1B1/3 Not Recommended Monitoring Recommended Dose Adjustment Recommended Amiodarone CCB Rosuvastatin (max 10mg) Anticonvulsants Antiarrhythmics Atorvastatin (max 40mg) Antifungals (azole) Digoxin PDE-5 inhibitors (not ED) Rifampin HIV medications St. John s Wort, Milk Thistle Cyclosporine Dexamethasone Midazolam Sirolimus Olysio [package insert]. 2015.

Simeprevir & Sofosbuvir Clinical Trial COSMOS trial treatment naïve and null responders to PEG/RBV SVR 12 rates: Metavir Score 0-2 Metavir Score 3-4 Sim/Sof x12 Sim/Sof + RBV x12 Sim/Sof x24 Sim/Sof +RBV x24 13/14 (93%) 26/27 (96%) 14/15 (93%) 19/24 (79%) 13/14 (93%) 25/27 (93%) 16/16 (100%) 28/30 (93%) Lawitz E, et al. (2014). Lancet.

Simeprevir Counseling Prescribing info recommends storing in original container Janssen in house studies reported stable in open dish at room temperature for 2-5 weeks Take with food Phototoxicity use sunscreen, avoid tanning beds Take missed dose as soon as possible, but skip in < 12 hours until next dose Serious rash can occur, discuss with provider if rash occurs Many drug interactions, ask your health care provider or pharmacist prior to starting any new medications Olysio [package insert]. 2015.

Sofosbuvir (Sovaldi ) Nucleotide polymerase NS5B inhibitor Treatment of Genotype 1, 2, 3, or 4 Dosing: 400mg once daily with or without food No dose adjustment Precautions Serious symptomatic bradycardia when administered with amiodarone Sovaldi [package insert]. 2015.

Sofosbuvir (Sovaldi ) Most Common Adverse Reactions Sofosbuvir + RBV fatigue (30-38%), headache (24-30%), nausea (13-22%), insomnia (15-16%), anemia (6-10%), pruritus (11-27%), decreased appetite (6%) Sofosbuvir + PEG/RBV - fatigue (55-59%), headache (36-44%), nausea (29-34%), insomnia (25-29%), anemia (12-21%), pruritus (17%), decreased appetite (18%) Serious Adverse Reactions Pancytopenia (more common with PEG/RBV) Severe depression Sovaldi [package insert]. 2015.

Sofosbuvir Drug Interactions Substrate of P-gp transporter and breast cancer resistance protein (BCRP) Drugs that induce P-gp in the intestine may result in decreased sofosbuvir plasma concentrations Not Recommended Amiodarone Anticonvulsants St. John s Wort HIV protease inhibitors Rifampin Sovaldi [package insert. 2015.

Amiodarone Interaction Occurred when amiodarone was coadministed with sofosbuvir + investigational NS5A inhibitor, sofosbuvir + simeprevir, and ledipasvir/sofosbuvir Bradycardia and fatal cardiac arrest have been reported Bradycardia typically occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients taking beta blockers, those with cardiac comorbidities or advanced liver disease are at increased risk. Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment. Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, confusion or memory problems. Harvoni [package insert]. 2015.

Sofosbuvir Clinical Trials Trial Patient Profile Regimen SVR 12 NEUTRINO N = 320 FISSION N = 499 POSITRON N = 278 FUSION N = 201 VALENCE N = 419 GT 1/4/5/6 Tx naïve GT 2/3 Tx naïve GT 2/3 Tx exp PEG ineligible GT 2/3 Tx exp GT 2/3 Tx naïve & Tx exp Sof + PEG/RBV x12 GT 1 89% (261/292) GT 1a 92% (206/225) GT 1b 82% (54/66) GT 4 96% (27/28) Sof + RBV x12 GT 2 95% (69/73) GT 3 56% (101/183) Sof + RBV x12 GT 2 93% (101/109) GT 3 61% (60/98) Sof + RBV x12 Sof + RBV x16 Sof + RBV x12 Sof + RBV x24 GT 2 82% (32/39) GT 3 30% (19/64) GT 2 89% (31/35) GT 3 62% (39/63) ( GT 2 93% (68/73) GT 3 84% (210/250) Sovaldi [package insert. 2015.

Sofosbuvir Counseling Prescribing info recommends storing in original container Gilead stability studies Environment Container Acceptable Duration Room temp (77 o F) No container 45 days Direct sunlight No container 2-3 days Office lights No container 3 months Take with or without food Take missed dose as soon as you remember if the same day Many drug interactions, ask your health care provider or pharmacist prior to starting any new medications Avoid pregnancy if using with RBV Sovaldi [package insert. 2015.

Ledipasvir/Sofosbuvir (Harvoni ) Approved for GT 1 (also for GT 3,4) Ledipasvir - a NS5A inhibitor Sofosbuvir - a nucleotide polymerase NS5B inhibitor Ledipasvir 90mg and Sofosbuvir 400mg Dosing - 1 tablet daily with or without food No dose adjustments Precautions Serious symptomatic bradycardia when administered with amiodarone Do not use with Sovaldi Common Adverse Reactions fatigue (13-18%), headache (11-17%), nausea (6-9%), diarrhea (3-7%), insomnia (3-6%) Harvoni [package insert]. 2015.

Harvoni Drug Interactions Ledipasvir is an inhibitor of the P-gp transporters and BCRP May increase absorption of P-gp and BCRP substrates Ledipasvir and Sofosbuvir are substrates of P-gp transporter and BCRP P-gp and BCRP inhibitors may reduce plasma concentrations Not Recommended Amiodarone Anticonvulsants HIV Antiretrovirals Stribild Tipranivir/ritonavir St. John s Wort Simeprevir Rosuvastatin Rifampin Other Interactions Acid reducing agents* Digoxin HIV Antiretrovirals Atripla Tenofovir + HIV protease inhibitor Harvoni [package insert]. 2015.

Harvoni Clinical Trials Trial Patient Profile Regimen SVR 12 (all pts) SVR 12 (cirrhotic) ION-1 N = 865 GT 1 Tx naïve LDV/SOF x12 LDV/SOF + RBV x12 LDV/SOF x24 LDV/SOF + RBV x24 99% (211/214) 97% (211/217) 98% (212/217 99% (215/217 94% (32/34) 100% (33/33) 94% (31/33) 100% (36/36) ION-2 N = 440 GT 1 Tx exp LDV/SOF x12 LDV/SOF + RBV x12 LDV/SOF x24 LDV/SOF + RBV x24 94% (102/109) 96% (107/111) 99% (108/109) 99% (110/111) 86% (19/22) 82% (19/22) 100% 22/22) 100% (22/22) ION-3 N = 647 GT 1 Tx naive LDV/SOF x8 HCV RNA < 6 mil HCV RNA 6 mil LDV/SOF + RBV x8 LDV/SOF x12 HCV RNA < 6 mil HCV RNA 6 mil 94% (202/215) 98% (121/123) 90% (83/92) 93% (201/216) 95% (206/216) 98% (129/131) 99% (84/85) Harvoni [package insert]. 2015.

Harvoni Counseling Prescribing info recommends storing in original container Gilead stability studies Environment Container Acceptable Duration Room temp (77 o F) No container 45 days Direct sunlight No container 2-3 days Office lights No container 3 months Take with or without food Take missed dose as soon as you remember if the same day Many drug interactions, ask your health care provider or pharmacist prior to starting any new medications Avoid pregnancy if using with RBV Harvoni [package insert]. 2015.

Ombitasvir/Paritaprevir/Ritona vir & Dasabuvir (Viekira Pak ) Genotype 1 (with or without RBV) Tab #1 2 tabs AM Ombitasvir (12.5mg) NS5A inhibitor Paritaprevir (75mg) NS3/4A protease inhibitor Ritonavir (50mg) CYP3A inhibitor Tab #2 1 tab AM & 1 tab PM (w/meal) Dasabuvir (250mg) - non-nucleoside NS5B polymerase inhibitor No dose adjustments Common Adverse Reactions fatigue (34%), nausea (22%), pruritus (18%), skin reactions (16%), insomnia (14%), asthenia (14%) Viekira Pak [package insert]. 2015.

Ombitasvir/Paritaprevir/Ritona vir (Technivie ) Genotype 4 (with RBV) Non-cirrhotic only Same as tablet #1 in Viekira Pak Dasabuvir has no effect in GT 4 Dosing 2 Tabs AM with food Technivie [package insert]. 2015.

Viekira Pak Contraindicated Moderate Severe hepatic impairment (Child-Pugh B or C) Substrates of CYP3A Moderate-Strong inducers of CYP3A Precautions Risk of hepatic decompensation and failure (increased w/ cirrhosis) ALT elevations (esp. w/ ethinyl estradiol) Risk of HIV protease inhibitor resistance (ritonavir) Many drug interactions Viekira Pak [package insert]. 2015

Viekira Pak Drug Interactions Paritaprevir: Inhibits UGT1, OATP1B1, OATP1B3, BCRP Metabolized by CYP3A Substrate of P-gp, BCRP, OATP1B1, OATP1B3 Ombitasvir: Inhibits UGT1 Metabolized by amide hydrolysis Substrate of P-gp, BCRP Ritonavir: Inhibits CYP3A4, BCRP Metabolized by CYP3A Substrate of P-gp Dasabuvir: Inhibits UGT1, BCRP Metabolized by CYP2C8 Substrate of P-gp, BCRP Viekira Pak [package insert]. 2015 Contraindicated Alfuosin Gemfibrozil Rifampin Carbamazepine Phenytoin Phenobarbital Ergot. derivatives Ethinyl Estradiol St. John s Wort Lovastatin Simvastatin Pimozide Efavirenz Sildenafil (for PAH) Midazolam Triazolam Not Recommended Voriconazole Darunavir/Ritonavir Lopinavir/Ritonavir Rilpivirine Salmeterol Fluticasone Dose Adjustment Quetiapine (1/6 dose) Ketoconazole (max 200mg) Rosuvastatin (max 10mg) Pravastatin (max 40mg) Monitoring Suboxone Alprazolam Furosemide Amlodipine

Viekira Pak & Technivie Clinical Trials Trial Patient Profile Regimen SVR 12 SAPPHIRE-I N = 631 SAPPHIRE-II N = 394 PEARL-I N = 135 PEARL-II N = 179 PEARL-III N = 419 PEARL-IV N = 305 TURQUOISE-II N = 380 GT 1a/1b; Tx naïve Non-cirrhotic GT 1a/1b; Tx exp Non-cirrhotic GT 4, Tx naïve & exp Non-cirrhotic GT 1b; Tx exp Non-cirrhotic GT 1b; Tx naïve Non-cirrhotic GT 1a; Tx naïve Non-cirrhotic GT 1a/1b; Tx naïve Cirrhotic Viekira + RBV x12 96% (308-322) Viekira + RBV x12 96% (166/173) Technivie +RBV x12 Technivie x12 Tx naïve 100% (42/42) Tx exp 100% (49/49) Tx naïve 91% (40/44) Viekira + RBV x12 100% (91/91) Viekira x12 100% (209/209) Viekira + RBV x12 97% (97/100) Viekira + RBV x12 Viekira + RBV x24 Viekira Pak [package insert]. 2015, Technivie [package insert]. 2015. GT 1a 89% (124/140) GT 1b 99% (67/68) GT1a 95% (115/121)

Viekira Pak Counseling Store at room temperature (<86 o F) Take with a meal Monitor for signs of hepatic decompensation and failure Avoid pregnancy if using with RBV Missed doses: Ombitasvir/paritaprevir/ritonavir tablet Take as soon as you remember if <12 hours since your missed dose, if >12 hours then skip the missed dose Dasabuvir tablet Take as soon as you remember if <6 hours since your missed dose, if >6 hours then skip the missed dose Many drug interactions, ask your health care provider or pharmacist prior to starting any new medications Viekira Pak [package insert]. 2015.

Daclatasvir (Daklinza ) Approved for GT 3 (with sofosbuvir) Available in 30mg and 60mg tablets NS5A inhibitor Dosing 60mg once daily with or without food Dose adjustment Drug interactions reduce to 30mg daily w/ strong CYP3A inhibitor and increase to 90mg w/ moderate CYP3A inducer Renal/Hepatic no dose adjustments Common Adverse Reactions headache (14%), fatigue (14%), nausea (8%), diarrhea (5%) Daklinza [package insert]. 2015.

Daclatasvir Drug Interactions Substrate of CYP3A Inhibitor of P-gp OATP1BI and OATP1B3, BCRP Contraindicated Dose Adjustment ( 30mg) Strong CYP3A Inhibitors Dose Adjustment ( 90mg) Mod CYP3A Inducers Monitor Phenytoin Atazanavir/Ritonavir Dexamethasone Digoxin (reduce digoxin) Carbamazepine Clarithromycin Efavirenz Dabigatran Rifampin Ketoconazole Modafinil Statins St. John s wort Nefazodone Nafcillin Voriconazole Daklinza [package insert]. 2015.

Daclatasvir Clinical Trials ALLY-3 Trial N = 152 Daclatasvir + Sofosbuvir x12 wk Patient Profile Tx naïve SVR 12 Tx exp SVR 12 All patients GT 3 All patients GT 3 Non-cirrhotic GT 3 Cirrhotic 90% (91/101) 86% (44/51) 89% (135/152) 98% (80/82) 92% (35/38) 96% (115/120) 58% (11/19) 69% (9/13) 63% (20/32) Daklinza [package insert]. 2015.

Daclatasvir Counseling Store at room temperature between 59-86 o F Take with or without food If you miss a dose take it as soon as you remember the same day Avoid pregnancy if using with RBV Many drug interactions, ask your health care provider or pharmacist prior to starting any new medications Daklinza [package insert]. 2015.

Treatment Guidelines - Ratings American Association for the Study of Liver Diseases (AASLD) & Infectious Diseases Society of America (IDSA) & International Antiviral Society - USA Rating System Used to Rate the Level of the Evidence and Strength of the Recommendation for Each Recommendation Classification Class I Class II Class IIa Class IIb Class III Description Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnostic evaluation, procedure, or treatment Weight of evidence and/or opinion is in favor of usefulness and efficacy Usefulness and efficacy are less well established by evidence and/or opinion Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful Level of Evidence Description Level A Data derived from multiple randomized clinical trials, meta-analyses, or equivalent Level B Level C Data derived from a single randomized trial, nonrandomized studies, or equivalent Consensus opinion of experts, case studies, or standard of care AASLD/IDSA/IAS USA. Treatment Guidelines. 2015.

Treatment Recommendations GT 1, Tx Naïve Genotype Tx History Cirrhosis Regimen x Weeks Rating 1a Naïve Non-cirrhotic Harvoni x12 Viekira + RBV x12 Sim/Sof +/- RBV x12 Daclat/Sof x12 1b Naïve Non-cirrhotic Harvoni x12 Viekira x12 Sim/Sof +/- RBV x12 Daclat/Sof x12 1a Naïve Cirrhotic Harvoni x12 Viekira + RBV x24 Sim/Sof +/- RBV x24 Q80k Daclat/Sof +/-RBV x24 1b Naïve Cirrhotic Harvoni x12 Viekira x12 Sim/Sof +/- RBV x24 Daclat/Sof +/- RBV x24 1B 1B 1B 2B 1B 2aB AASLD/IDSA/IAS USA. Treatment Guidelines. 2015.

Treatment Recommendations GT 1, Tx Experienced (PEG/RBV) Genotype Tx Hx Cirrhosis Regimen x Weeks Rating 1a Exp (PEG/RBV) Non-cirrhotic Harvoni x12 Viekira + RBV x12 Sim/Sof x12 Daclat/Sof x12 1b Exp (PEG/RBV) Non-cirrhotic Harvoni x12 Viekira x12 Sim/Sof x12 Daclat/Sof x12 1a Exp (PEG/RBV) Cirrhotic Harvoni x24 Harvoni + RBV x12 Viekira + RBV x24 Sim/Sof +/- RBV x24 (neg Q80K) Daclat/Sof +/- RBV x24 1b Exp (PEG/RBV) Cirrhotic Harvoni x24 Harvoni + RBV x12 Viekira x12 Sim/Sof +/- RBV x24 Daclat/Sof +/- RBV x24 AASLD/IDSA/IAS USA. Treatment Guidelines. 2015. 2aB 2aB 2aB 1B 2aB 2aB 1B 2aB 2aB

Recommendations GT 1, Tx Experienced (DAA) Genotype Tx History Cirrhosis Regimen x Weeks Rating 1a Exp (Sof/RBV) Non-cirrhotic Harvoni x12 2bC 1b Exp (Sof/RBV) Cirrhotic Harvoni + RBV x12 2aC 1a or 1b Exp (PI +PEG/RBV) Non-cirrhotic Harvoni x12 Sof/Daclat x12 1a or 1b Exp (Sim/Sof) Non-cirrhotic Harvoni + RBV x12 1a or 1b Exp (PI +PEG/RBV) Cirrhotic Harvoni x24 Harvoni + RBV x12 Daclat/Sof +/- RBV x24 1a or 1b Exp (Sim/Sof) Cirrhotic Harvoni +RBV x24 1a or 1b Exp (NS5A inhibitor) Non-cirrhotic Defer treatment 2bC 2aB 2aB 1a or 1b Exp (NS5A inhibitor) Cirrhotic Test for NS3 PI and NS5A inhibitor resistance Tx duration x24 Add RBV 2bC AASLD/IDSA/IAS USA. Treatment Guidelines. 2015.

Treatment Recommendations GT 2 & 3 Genotype Tx History Cirrhosis Regimen x Weeks Rating 2 Naïve Non-cirrhotic Sof + RBV x12 Daclat/Sof x12 (RBV intolerant) 2 Naïve Cirrhotic Sof + RBV x16 2bC 2 Exp (PEG/RBV) Non-cirrhotic or Cirrhotic 2 Exp (Sof + RBV) Non-cirrhotic or Cirrhotic 3 Naïve Non-cirrhotic Or Cirrhotic Sof + RBV x16 or x24 Sof + PEG/RBV x 12 Daclat/Sof +/- RBV x24 (IFN ineligible) Sof + PEG/RBV x12 Daclat/Sof +/- RBV x12 (non-cirrhotic) Daclat/Sof +/- RBV x24 (cirrhotic) Sof + PEG/RBV x 12 Sof + RBV x24 (IFN ineligible) 3 Exp (PEG/RBV) Non-cirrhotic Daclat/Sof x12 3 Exp (PEG/RBV) Cirrhotic Daclat/Sof + RBV x24 Sof + PEG/RBV x12 3 Exp (Sof + RBV) Daclat/Sof + RBV x24 (IFN ineligible) Sof + PEG/RBV x12 AASLD/IDSA/IAS USA. Treatment Guidelines. 2015. 2aB 2aB 2aC 2aC 2aC 2aC 2aC 2aC

Treatment Recommendations GT 4 & 5/6 Genotype Tx History Cirrhosis Regimen x Weeks Rating 4 Naïve Non-cirrhotic or Cirrhotic 4 Exp (PEG/RBV) Non-cirrhotic or Cirrhotic 5,6 Naïve Non-cirrhotic or Cirrhotic Harvoni x12 Technivie + RBV x12 Sof + RBV x24 Sof + PEG/RBV x12 Harvoni x12 Technivie + RBV x12 Sof +PEG/RBV x12 Sof + RBV x24 Harvoni x12 Sof + PEG/RBV x12 5,6 Exp (PEG/RBV) Harvoni x12 Sof + PEG/RBV x12 2bB 1B 2aB 2B 2aB 2aB 2aB 2aB 2aB 2aB 2aC 2aC AASLD/IDSA/IAS USA. Treatment Guidelines. 2015.

Choosing Treatment Patient specific Intolerances/allergies Baseline labs (RBV or interferon ineligible) Concomitant medications Cost/Insurance AWP (28 day supply) Daklinza $25,200 Harvoni $37,800 Olysio $26,544 Sovaldi $33,600 Technivie $30,661 Viekira Pak $33,328 Red Book Online (electronic version). 10/30/2015

Direct Acting Antiviral Drug Interactions (not fully inclusive) Daclatasvir Ledipasvir Viekira Simeprevir Sofosbuvir Acid Reducers X X Alfuzosin X Amiodarone X X X X X Anticonvulsants X X X X X Azole antifungals X X X Suboxone X Calcium channel blockers X X X Digoxin X X X Ethinyl estradiol X Furosemide X Gemfibrozil X Glucocorticoids X X (inhaled) X Macrolides X X Milk Thistle X PDE 5 inhibitors X X Rifampin X X X X X Salmeterol X Sedatives X X St. John s wort X X X X X Statins X X X X Adapted from: AASLD/IDSA/IAS USA. Treatment Guidelines. 2015.

Hepatitis C Resources AASLD/IDSA Guidelines http://www.hcvguidelines.org/ University of Liverpool, Hepatitis C drug interactions - http://www.hep-druginteractions.org/ VA Hepatitis C Information for patients and providers http://www.hepatitis.va.gov/ University of Washington, Hepatitis C online http://www.hepatitisc.uw.edu/

References AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 10/08/15. Advances in Medications to Treat Hepatitis C. Updated September 2015. Retrieved from: http://hepc.liverfoundation.org/treatment/the-basics-about-hepatitis-c-treatment/advances-inmedications/. Accessed 11/01/15. CDC. Testing for HCV infections: An update of guidance for clinicians and laboratories. MMWR. 2013: 62(18) Daklinza [package insert]. Princeton, NJ. Bristol-Myers Squibb Company. 2015. Harvoni [package insert]. Foster City, CA: Gilead Sciences. 2015. Hepatitis C FAQs for Health Professionals. Updated Oct 14, 2015. Retrieved from: http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm#section1. Accessed 10/31/15. Hepatitis C Online: Ribavirin Drug Summary. 2015. http://www.hepatitisc.uw.edu/page/treatment/drugs/ribavirin-drug. Accessed Nov 1, 2015. Hepatitis C Online: Ribavirin Drug Summary. 2015. http://www.hepatitisc.uw.edu/page/treatment/drugs/ribavirin-drug. Accessed Nov 1, 2015. Hepatitis C Online: Hepatitis C Online: Peginterferon alpha-2a Drug Summary. 2015. http://www.hepatitisc.uw.edu/page/treatment/drugs/ribavirin-drug. Accessed Nov 1, 2015.

References Hepatitis C Online: Hepatitis C Online: Peginterferon alpha-2b Drug Summary. 2015. http://www.hepatitisc.uw.edu/page/treatment/drugs/ribavirin-drug. Accessed Nov 1, 2015. Lam BP, Jeffers T, Younoszai Z, et al. 2015. The changing landscape of Hepatitis C virus therapy: focus on interferon-free treatment. Ther Adv Gastroenterol. 8(5) 298-312. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A, et al. (2014). Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naïve patients: the COSMOS randomized study. Lancet. 394 (9956). 1756-1765. Mandal A. Hepatitis C History. Updated April 26, 2013. Retrieved from: http://www.newsmedical.net/health/hepatitis-c-history.aspx. Accessed 11/01/15 Messina JP, Humphreys I, Flaxman A, et al. 2015. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 61(1). 77-87. Olysio [package insert]. Titusville, NJ: Jansen Therapeutics. 2015. Sovaldi [package insert]. Foster City, CA: Gilead Sciences. 2015. Red Book Online (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: 10/30/2015). Technivie [package insert]. Chicago, IL: AbbVie Inc. 2015. Viekira Pak [package insert]. Chicago, IL: AbbVie Inc. 2015.