Objectives. Disclosures 1/26/2016. Which of These Drugs is FDA Approved for the Treatment of Genotype 1 Infection?

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1 New Horizons: Navigating the Changing Tides of Hepatitis C Therapy Jennifer Andres, PharmD, BCPS Clinical Assistant Professor of Pharmacy Practice Temple University School of Pharmacy Objectives Review epidemiology, pathophysiology, and treatment of Hepatitis C Compare FDA-approved treatment options for genotype 1 infections Evaluate recommended treatment strategies for genotype 1 infections Describe the role of a pharmacist in the treatment of Hepatitis C Disclosures I, Jennifer Andres, have no conflicts of interest or financial relationships to disclose Who dispenses medications for Hepatitis C at your practice? Who performs Hepatitis C testing at your practice? Which of These Drugs is FDA Approved for the Treatment of Genotype 1 Infection? Simeprevir Sofosbuvir Daclatasvir Interferon SR is a 38 year old African American female patient who presents for initial evaluation for a newly diagnosed Hepatitis C infection. SR weighs 70 kg and stands 5 3. Allergies: furosemide (swelling of mouth), sulfamethoxazole/trimethoprim (hives) PMH: Hepatitis C (newly diagnosed), depression, GERD, acne, exercise-induced asthma Current Medications: Albuterol Inhaler 1 puff PO Q4-6H PRN Omeprazole 40 mg PO daily Citalopram 40 mg PO daily Ethinyl estradiol/drosperinone PO daily Pertinent Labs/Tests: Anti-HCV + HCV RNA > 2 million copies Genotype: 1a AST 32/ALT 45 INR 1.0 Liver Biopsy: No cirrhosis present 1

2 HCV Epidemiology Most common blood-borne pathogen 170 million people worldwide 3.2 million people in the US Nearly 75% of infected people may not be identified yet Impact of undiagnosed and untreated HCV expected to increase dramatically Diagnosis may be an incidental findingand may not be made until disease progression Likely to become a chronic infection Primary cause of liver transplant and hepatocellular carcinoma HCV Etiology HCV is a single-stranded RNA virus of the family Flaviviridae Lacks a proofreading polymerase Replicates within hepatocytes and is not directly cytopathic HCV is differentiated into six major genotypes Genotypes are further classified into subtypes (a, b, c, etc.) Therapeutic response and drug treatment is based on infecting genotype All can lead to cirrhosis, end-stage liver disease, or HCC Deming P, et al. Pharmacotherapy, 9e HCV Genotype Distribution HCV Risk Factors In the US, >70% are genotype 1 infections Center for Disease Prevalence 9 Injection-drug use Blood transfusion before 1992 Healthcare-associated transmission Sexual contact Multiple sexual partners Coinfection with STDs or HIV? Acupuncture, tattooing, and body piercing? Deming P, et al. Pharmacotherapy, 9e HCV Pathophysiology Acute infection leads to chronic infection Immune response is insufficient to eradicate the virus Rapid viral diversification Genomic mutations detectable within 1 year Diagnostic Tests HCV antibody HCV nucleic acid test Genotype Genetic polymorphisms Assessments of liver disease Liver biopsy FibroScan Serum markers of fibrosis APRI, FIB4, Fibrosure, FibroTest, HepaScore Imaging Ultrasonography, ARFI, MRE, MRI, CT scan Clinical findings 2

3 CDC Recommended Screening Born between Injection or intranasal illicit drug use Chronic hemodialysis Receipt of tattoo in an unregulated setting Child of an HCV-infected mother Blood transfusion or organ transplant before 1992 Clotting factor before 1987 Incarceration HIV Unexplained chronic liver disease HCV Goals of Treatment Eradicate HCV RNA Sustained virologic response (SVR) Undetectable RNA after treatment (12-24 weeks) Determines cure Decrease mortality, need for liver transplant, hepatocellular carcinoma rates, and hepatic-related complications Improve quality of life Deming P, et al. Pharmacotherapy, 9e Who to Treat? ALL HCV infected patients Except patients with short life expectancy that could not be remediated with HCV treatment Drug Abbrev Approval Date Peginterferon (Pegasys, PegIntron) PEG-IFN 2001; 2002 Interferon Therapeutic Class Ribavirin (Copegus, others) 2001 Antiviral Agent Boceprevir (Victrelis ) BOC 2011 Protease Inhibitor Telaprevir(Incivek ) TVR 2011 Protease Inhibitor Simeprevir (Olysio ) SMP 2013 Protease Inhibitor (2 nd generation) Sofosbuvir (Sovaldi ) SOF 2013 Polymerase Inhibitor Ledipasvir/Sofosbuvir (Harvoni ) Ombitasvir/Paritaprevir/ Ritonavir and Dasabuvir (Viekira Pak ) LDV/SOF 2014 Combination Product OMB/PTV/r + DSV; PrOD 2014 Combination Product Daclatasvir (Daklinza ) DCV 2015 NS5A inhibitor Ombitasvir/Paritaprevir/ Ritonavir (Technivie ) OMB/PTV/r 2015 Combination Product 16 The Old The New Class Simeprevir(Olysio ) NS3/4A Protease Inhibitor Drug Interactions Substrate of 3A4, P-gp, SLCO1B1 Inhibits 1A2, P-gp, SLCO1B1 Interferon Products Ribavirin First Generation Protease Inhibitors OralDirect Acting Antivirals Dosing Derm: Skin rash, pruritis, photosensitivity Hepatic: Increased serum bilirubin 150 mg PO daily Other Information Sulfonamide moiety Increased risk for reaction in East Asian population Test for Q80K variant? Olysio[package insert]. Titusville, NJ. Janssen

4 Sofosbuvir(Sovaldi ) Ledipasvir/Sofosbuvir(Harvoni ) Class Polymerase Inhibitor Ledipasvir Sofosbuvir Drug Interactions Substrate of P-gp Amiodarone Class NS5A inhibitor Polymerase Inhibitor Dosing 90 mg once daily 400 mg once daily Dosing Fatigue, headache, nausea 400 mg PO daily Other Information Prodrug(converted via intracellular metabolism) Active moiety cleared renally High barrier for resistance Pangenotypic agent Drug Interactions Other Information Fatigue and headache P-glycoprotein substrates Acid suppressing agents Rosuvastatin Amiodarone Coformulated combination tablet Pangenotypic agent Contains sofosbuvir all warnings still applicable Sovaldi[package insert]. Foster City, CA. Gilead Sciences Harvoni[package insert]. Foster City, CA Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir(Viekira Pak ) Ombitasvir Paritaprevir Ritonavir Dasabuvir Class NS5A inhibitor NS3/4A protease inhibitor Booster for paritaprevir NS5B polymerase inhibitor Dosing 12.5 mg daily 75 mg daily 50 mg daily 250 mg BID Drug Interactions Other Information Fatigue, nausea, pruritus, skin reactions, insomnia, and asthenia Ritonavir is a potent 3A4 inhibitor Concomitant use of inhaled salmeterolcan lead to increased QTc interval Concomitant use of other agents that prolong the QTcinterval can further increase this risk Concomitant use of ethinylestradiol-containing medications can result in significant elevations in hepatic aminotransferase levels Two combination tablets (ombitasvir/paritaprevir/ritonavir) once daily with one tablet of dasabuvir twice daily with food In HIV positive patients, must use with fully active HIV regimen Ethinyl estradiol products should be discontinued prior to use Increased chance of significant drug interactions due to ritonavir Warning for liver injury added 10/2015 ViekiraPak [package insert]. North Chicago, IL. AbbVie Class Drug Interactions Dosing Daclatasvir (Daklinza ) NS5A inhibitor Substrate of CYP3A4 (major), P-glycoprotein Inhibits BCRP, P-glycoprotein, SLCO1B1 CNS: Fatigue, headache GI: Nausea, diarrhea, increased serum lipase 60 mg PO daily Dosing Adjustments Strong inhibitors of CYP3A:30 mg once daily Moderate CYP3A inducers:90 mg once daily Strong CYP3A inducers: Concomitant use is contraindicated Other Information Daklinza[package insert]. March 2015 Currently approved for genotype 3 only. Expect more approvals in the future Commercially available as 30mg and 60mg tablets Amiodaroneprecaution (due to sofosbuvircomponent of regimen) Treatment Response HCV Therapeutic Decisions SVR 15-20% Interferon monotherapy SVR 40-55% PEG-IFN + SVR 65-75% Triple therapy with 1 st generation protease inhibitors SVR >90% Interferon free regimens AASLD and IDSA have collaborated on Practice Guidelines Guidelines are updated as data is released Available free at

5 GT First Line Regimen for Treatment Naïve Patients* Duration 1a DCV/SOF +/- weight-based (with cirrhosis) LDV/SOF OMB/PTV/r + DSV + weight-based 1b SOF + SIM +/-weight-based DCV/SOF +/- weight-based (with cirrhosis) LDV/SOF What trials led to these recommendations? OMB/PTV/r + DSV + weight-based (with cirrhosis) SOF + SIM *Presented in alphabetical order 25 Drug Regimen DCV/SOF +/-wtbased Clinical Trial Design ALLY 2 Phase 3, open-label study Treatment naïve and experienced HIV/HCV co-infected n=395 DCV/SOF for 8- ALLY 1 Phase 3study Advanced cirrhotic and postliver transplant n= 60; n=53 DCV/SOF + x Summary of Results (SVR12) 8 weeks 76% (31/41) 96% (80/83) Advanced cirrhosis 82% (37/45) Post liver transplant 95% (39/41) Transplant Advanced Cirrhosis DCV/SOF +/- : % Obtaining SVR ALLY-1 A Wyleset al.n EnglJ Med Poordadet al. Vienna, Austria Sulkowski MS, et al. N EnglJ Med Phase2b study, open-label study Treatment naïve n=211 DCV/SOF (+/- x 2 weeks) Endpoint: SVR12 SOF lead in, DCV/SOF 100% (15/15) DCV/SOF 100% (14/14) DCV/SOF/ 100% (15/15) 27 8 weeks ALLY Drug Regimen Clinical Trial Design LDV/SOF ION 1 Phase 3, randomized, openlabel study Cirrhotic patients included n=865 SOF/LDV ± for 12 or 24 weeks Summary of Results (SVR12) LDV/SOF 99% (211/214) LDV/SOF/ 97% (211/217) LDV/SOF 24 weeks 98% (212/217) LDV/SOF/ 24 weeks 99% (215/217) LDV/SOF LDV/SOF/ 8 weeks LDV/SOF 8 weeks LDV/SOF/ 24 weeks LDV/SOF +/- : % Of Patients Obtaining SVR ION-3 ION 3 Phase 3, randomized, openlabel study Cirrhoticpatients not included n=647 SOF/LDV ± for 8 or 12 weeks LDV/SOF 8 weeks 94% (202/215) LDV/SOF/ 8 weeks 93% (201/216) LDV/SOF 96% (206/216) LDV/SOF 24 weeks LDV/SOF/ LDV/SOF ION-1 AfdhalN, et al. N EnglJ Med 2014;370: KowdleyKV, et al. N EnglJ Med 2014;370:

6 Regimen OMB/PTV/r + DSV+/- wtbased Clinical Trials Design SAPPHIRE- I Multicenter, randomized, double-blind, placebocontrolled N=631 OMB/PTV/r + DSV + for PEARL III Phase 3, randomized, double-blind study Genotype 1b patients included n=419 OMB/PTV/r + DSV +/- for PEARL- IV Phase 3, randomized, double-blind study Genotype 1a patients included n=305 OMB/PTV/r + DSV +/- for 12weeks TURQUOISE -II Phase 3, randomized, open-label study Treatment naïve and experienced patients included with CTP Class A cirrhosis n=380 OMB/PTV/r + DSV + for 12 or 24 weeks Feld JJ et al.n EnglJ Med.2014 FerenciP et al.n EnglJ Med.2014 PoordadF et al. N EnglJ Med.2014 Regimen Clinical Trials Summary of Results (SVR12) OMB/PTV/r + DSV+/- wt-based Feld JJ et al.n EnglJ Med.2014 FerenciP et al.n EnglJ Med.2014 PoordadF et al. N EnglJ Med.2014 SAPPHIRE- I 96.2% (455/473) PEARL III With 99.5% (209/210) Without 99% (207/209) PEARL- IV With 97% (97/100) Without 90.2% (185/205) TURQUOISE -II 92% (191/208) 24 weeks 96% (165/172) TURQUOISE - II 24 weeks TURQUOISE - II PEARL - IV No PEARL - IV PrOD+/-: % Of Patients Obtaining SVR Regimen Clinical Trials SOF + SIM +/-wtbased OPTIMIST -1 Design Phase 3, randomized, open label Treatment-naive and - experienced patients without cirrhosis n=310 SIM/SOF x 8- Summary of Results (SVR12) 8weeks 85% (88/103) 97% (112/115) PEARL-III No PEARL-III SAPPHIRE-I OPTIMIST -2 Phase 3, randomized, open label, single arm Treatment-naive and - experienced patients with cirrhosis n=103 SIM/SOF x (treatment naïve) 88% (44/50) KwoP et al. Vienna, Austria LawitzE et al. Vienna, Austria SIM/SOF: % Of Patients Obtaining SVR Drug Regimen Clinical Pearls DCV/SOF Watch out for drug interactions! Bradycardia? DCV only FDA approved for genotype 3 infections OPTIMIST-2 OPTIMIST-1 OPTIMIST-1 8 weeks LDV/SOF Co-formulated combination product Acid suppressing agents may cause absorption problems Bradycardia? OMB/PTV/r + DSV +/- wt-based SOF + SIM +/- wt-based Watch out for drug interactions May require in regimen QTc prolongation? Contains active-hiv agent Caution with ethinyl estradiol Contraindicated in Class B and C cirrhosis Check for Q80K polymorphism Photosensitivity? Drug interactions may be problematic 36 6

7 Harder to Treat Populations Pipeline Agents Cirrhosis Status Compensated Decompensated Treatment experience Resistance CKD/dialysis HIV/HCV Coinfection Transplant Submitted for FDA approval in 2015 Grazoprevir/elbasvir Sofosbuvir/velpatasvir Role of the Pharmacist Counsel patients on risk factor reduction and avoidance of factors that may worse hepatic function Screen for drug interactions Ensure appropriate dosing and duration of drug therapy based on patient specific factors (concomitant disease states; renal function; hepatic function; concomitant drug therapy) Counsel patients on side effect profile of agents Encourage adherence Stay up to date on new agents/pipeline agents Which of These Drugs is FDA Approved for the Treatment of Genotype 1 Infection? Simeprevir Sofosbuvir Daclatasvir Interferon SR is a 38 year old African American female patient who presents for initial evaluation for a newly diagnosed Hepatitis C infection. SR weighs 70 kg and stands 5 3. Allergies: furosemide (swelling of mouth), sulfamethoxazole/trimethoprim (hives) PMH: Hepatitis C (newly diagnosed), depression, GERD, acne, exercise-induced asthma Current Medications: Albuterol Inhaler 1 puff PO Q4-6H PRN Omeprazole 40 mg PO daily Citalopram 40 mg PO daily Ethinyl estradiol/drosperinone PO daily Pertinent Labs/Tests: Anti-HCV + HCV RNA > 2 million copies Genotype: 1a AST 32/ALT 45 INR 1.0 Liver Biopsy: No cirrhosis present What are the recommended treatments for patients with genotype 1a infections? What specific factors would influence our choice of therapy for this patient? What regimen should be started for this patient? How long should therapy be continued? 7

8 References Deming P, et al. Pharmacotherapy, 9e Olysio[package insert]. Titusville, NJ. Janssen Sovaldi[package insert]. Foster City, CA. Gilead Sciences Harvoni[package insert]. Foster City, CA ViekiraPak [package insert]. North Chicago, IL. AbbVie Daklinza [package insert]. Princeton, NJ. Bristol Myers Squibb WylesDL, RuanePJ, Sulkowski MS, et al. Daclatasvirplus sofosbuvir for HCV in patients coinfectedwith HIV-1.N EnglJ Med PoordadF, Schiff ER, VierlingJM et al. Daclatasvir, sofosbuvir, and ribavirin combination for HCV patients with advanced cirrhosis or postransplantrecurrence: phase 3 ALLY-1 study. [Abstract L08.] 50th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22-16, 2015; Vienna, Austria. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvirplus sofosbuvir for previously treated or untreated chronic HCV infection. N EnglJ Med.2014b;370(3): Afdhal N, ZeuzemS, KwoP, et al. Ledipasvirand sofosbuvir for untreated HCV genotype 1 infection. N EnglJ Med.2014;370(20): Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvirand sofosbuvir for 8 or for chronic HCV without cirrhosis. N EnglJ Med. 2014;370(20): Feld JJ, KowdleyKV, CoakleyE, et al. Treatment of HCV with ABT-450/r-ombitasvirand dasabuvirwith ribavirin.n EnglJ Med.2014;370(17): FerenciP, Bernstein D, LalezariJ, et al. ABT-450/r-ombitasvirand dasabuvirwith or without ribavirin for HCV.N EnglJ Med.2014;370(21): PoordadF, Hezode C, Trinh R, et al. ABT-450/r-Ombitasvirand Dasabuvirwith Ribavirin for Hepatitis C with Cirrhosis.N EnglJ Med.2014;[Epubahead of print] KwoP, GitlinN, NahassR et al. A phase 3, randomised, open-labe study to evaluate the efficacy and safety of 8 and of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-naive and -experienced patients with chronic HCV genotype 1 infection without cirrhosis: OPTIMIST-1. 50th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22-26, 2015;S270; Vienna, Austria. LawitzE, MatusowG, DeJesus E et al. A phase 3, open-label, single-arm study to evaluate the efficacy and safety of of simeprevir (SMV) plus sofosbuvir (SOF) in treatment-naive or -experienced patients with chronic HCV genotype 1 infection and cirrhosis: OPTIMIST th Annual Meeting of the European Association for the Study of the Liver (EASL). April 22-26, 2015;S264; Vienna, Austria. Questions 8