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Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto Protease Inhibitors in Chronic Hepatitis C: An Update.

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Presentation on theme: "Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto Protease Inhibitors in Chronic Hepatitis C: An Update."— Presentation transcript:

1 Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto Protease Inhibitors in Chronic Hepatitis C: An Update COMPLETE SLIDE DECK (Chapters 1 – 6) November 2012

2 Robert P. Myers, MD, MSc Associate Professor, Liver Unit Division of Gastroenterology University of Calgary Management of Hepatitis C: Updated Guidelines from the Canadian Association for the Study of the Liver (CASL)

3 Objectives: HCV Management  Review updated CASL recommendations for management of HCV genotype 1*  Burden of HCV in Canada  Pre-treatment assessment  Triple therapy including boceprevir and telaprevir  Adverse effects  Drug-drug interactions  Antiviral resistance * Recommendations for non-1 genotypes are unchanged from the 2007 CASL HCV guidelines.

4 Burden of HCV in Canada  Significant medical and economic burden  Seroprevalence unknown Risk GroupPopulationPrevalencePrevalent CasesProportion of Cases IDU, total268,20052%140,00058% Current IDU84,40062%52,50022% Previous IDU183,80048%87,50036% Transfusion3,325,7000.8%25,90011% Hemophilia2,20040%9000.4% Other27,624, %75,80031% Total31,220,5000.8%243,000100% Remis RS. PHAC 2007

5 Burden of HCV in Canada  ~8,000 incident cases annually (80% IDUs)  Proportion diagnosed unclear (<80%)  HCV-related complications rising  Insufficient manpower to treat all cases Remis et al. PHAC Year Cirrhosis Decomp HCC Transplant Modelled incidence

6 Davis GL et al. Gastroenterology 2010; 138(2): * Assumes 30% Dx & up to 25% Rx’d in Outcomes at  Antiviral Therapy Must be Maximized to Make an Impact Liver-related death vs. no treatment (%) 0Current*25%50%75%100% Proportion of population treated 80% SVR rate 60% SVR rate 40% SVR rate 68% ↓ 34% ↓

7 Burden of HCV in Canada: CASL Recommendations  A large population-based seroprevalence survey should be conducted to accurately define the prevalence of hepatitis C in Canada. The design of the study should include populations with an increased risk of hepatitis C, particularly IDUs and immigrants from endemic countries.  Increased resources are necessary to improve hepatitis C treatment capacity in Canada, including the training of expert treaters and public funding for treatment nurses. Myers RP et al. Can J Gastro 2012; 26(6):359-75

8 Who Should Be Treated? CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

9  All patients with chronic HCV, particularly those with liver fibrosis, should be considered candidates for antiviral therapy.  Patients with extrahepatic manifestations of HCV should be considered for antiviral therapy.  Persistently normal ALT does not exclude significant liver disease nor preclude the need for antiviral therapy. Who Should Be Treated? CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

10  Some fibrosis assessment necessary  Prognosis  Necessity of treatment  Surveillance for HCC & varices  F2 threshold less important with improved therapies  Biopsy is imperfect  Sampling error; variability in pathologic interpretation  Numerous noninvasive alternatives to biopsy Bedossa P et al. Hepatology 2003; 38(6): Pre-Treatment Assessment: Is Liver Biopsy Really Necessary?

11 Test (Reference) Components Cut-off F2-F4 vs. F0-F1 Sensitivity/specificity F2-F4 vs. F0-F1 FibroScan (Castera, 2005) Liver stiffness by transient elastography ≥7.1 kPa67% / 89% APRI (Shaheen, 2007) AST/ULN x 100 Platelets ≥0.5 ≥0.7 ≥1.5 81% / 50% 84% / 70% 35% / 91% FibroTest (Poynard, 2004) α2M, haptoglobin, apo-A1, GGT, bilirubin ≥0.5856% / 83% FibroSpect II (Patel, 2004) α2M, HA, TIMP-1≥0.3677% / 73% Hepascore (Adams, 2005) α2M, HA, GGT, bilirubin≥0.5089% / 63% FibroMeter (Leroy, 2005) α2M, HA, AST, platelets, PT, urea ≥0.5075% / 78% Pre-Treatment Assessment: Non-invasive Measures of Fibrosis

12  Assessment of Disease Severity  All patients with HCV should have an assessment for the severity of liver fibrosis. Acceptable methods include liver biopsy, TE (FibroScan), and serum biomarker panels (e.g. APRI, FibroTest, Fibrometer), either alone or in combination.  Alternatively, cirrhosis can be confidently diagnosed in some patients with clear clinical or radiographic evidence. Pre-Treatment Assessment: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

13  Virologic Testing  HCV RNA and genotype testing are essential to the management of patients with chronic hepatitis C.  HCV RNA testing should be performed using a sensitive quantitative assay (lower limit of detection ≤ IU/mL) with a broad dynamic range. Standardized results should be expressed in IU/mL and be available within a maximum of 7 days in order to facilitate management decisions.  Although genotype 1b has higher response rates vs. genotype 1a, testing for HCV subtype is not indicated  This may change with newer DAAs available in the future Pre-Treatment Assessment: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

14 Ge. Nature Suppiah. Nat Genet Tanaka. Nat Genet Thomas. Nature  Single-nucleotide polymorphisms (SNPs) on chromosome 19  Encodes IFN-λ3  Associated with viral clearance  ~50% of ethnic variation in SVR rates  Strongest pre-treatment predictor of SVR, but on-treatment response more important Interleukin 28B (IL28B) T/T 102 T/C 433 C/C 336 European- Americans P=1.06x SVR (%) 70 T/C 91 C/C 30 African- Americans 14 T/C 35 C/C 26 Hispanics P=2.06x10 -3 P=4.39x10 -3 P=1.37x T/C 559 C/C 392 Combined rs SVR (%)Non-SVR (%) Numbers on bars represent n

15  IL28B Genotyping  The IL28B genotype may provide valuable information regarding the likelihood of SVR and the probability of qualifying for shortened treatment duration in previously untreated patients with genotype 1.  The role of IL28B genotyping is limited in treatment- experienced patients and those with genotypes other than 1 and 4.  A non-favourable IL28B genotype does not preclude antiviral therapy. Pre-Treatment Assessment: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

16  Triple therapy including peginterferon (PEG-IFN), ribavirin (RBV), and a protease inhibitor (telaprevir or boceprevir) is the new standard of care in treatment-naïve and previous treatment failures.  Boceprevir (800 mg every 8 hours with food) is administered after a 4-week lead-in period of PEG-IFN and RBV. Duration of therapy depends on patient characteristics and treatment response.  Telaprevir (750 mg every 8 hours with non-low fat food) should be started simultaneously with PEG-IFN and RBV and given for the initial 12 weeks of therapy. Antiviral Therapy for HCV Genotype 1: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

17  RGT - the tailoring of treatment duration based on early viral kinetics - can be employed in selected patient subgroups.  Boceprevir: HCV RNA negative at weeks 8 through 24  Telaprevir: HCV RNA negative at weeks 4 through 12  SVR rates of ~90% have been reported with 24 to 28 weeks of therapy in patients qualifying for RGT.  Partial responders treated with telaprevir, patients with cirrhosis, and prior null responders should not receive RGT. Response-Guided Therapy (RGT): CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

18  Adherence to treatment and to futility rules, and close monitoring of concomitant drugs and side effects are particularly important with PI-based therapy.  Optimal management of this population should be conducted by well-trained, experienced personnel. Adherence to Antiviral Therapy: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

19  Strict adherence to futility rules is vital to limit exposure to potential side effects of these costly therapies that will not achieve SVR, and to reduce emergence of antiviral resistance.  All therapy – including PEG-IFN and RBV – must be discontinued if futility rules are met:  Boceprevir: HCV RNA ≥100 IU/mL at week 12 or detectable at week 24  Telaprevir: HCV RNA >1,000 IU/mL at week 4 or 12, or detectable at week 24  Identical futility rules apply to treatment-naïve and treatment-experienced patients. Futility Rules: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

20 1,230 Slide courtesy of Dr. J. Feld. 1 W0W1W2W3W4 If futility rules met, RNA is rising! Stop therapy! ,800, % reduction: Continue? 475 HCV RNA (IU/mL) Futility Rules Indicate Treatment Failure Even if the Viral Load Has Declined

21  PI-based therapy associated with more adverse effects than PEG-IFN and RBV dual therapy  No data to support switching from one PI to another to manage toxicity  Major adverse effects differ by PI  Boceprevir: anemia (~50%), dysgeusia (~40%)  Telaprevir: anemia (~40%), rash (~40%), anorectal symptoms (~30%) Adverse Effects of the Protease Inhibitors (PIs) Myers RP et al. Can J Gastro 2012; 26(6):359-75

22  Treatment with PIs should be supervised by experienced personnel and adverse effects monitored closely.  Close monitoring of hemoglobin levels is essential during antiviral treatment for HCV, particularly during the administration of PIs.  Management of anemia may include any of the following strategies: RBV dose reduction (first line), transfusion of packed red blood cells, and/or erythropoietin administration. Adverse Effects of the Protease Inhibitors (PIs): CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

23  Boceprevir and telaprevir are substrates and inhibitors of CYP3A4*  CYP3A4 metabolizes many common drugs  Potential increased drug concentrations with PI co- administration  Drugs that induced CYP3A4 may reduce PI concentration (i.e. antiviral treatment efficacy)  Numerous potential DDIs with PI-based therapy  Antiarrhythmics, anticoagulants, anticonvulsants, antihistamines, antibacterials, antiretrovirals, statins, herbal products, immunosuppressants, OCPs, phosphodiesterase inhibitors, and some sedatives/hypnotics * Minor elimination pathways include P-glycoprotein and aldoketoreductase. Drug-Drug Interactions (DDIs)

24  Prior to the initiation of PIs, potential DDIs must be considered, including those attributable to prescription and over-the-counter pharmaceuticals and herbal preparations.  Review product monographs and useful online resources for potential DDIs prior to initiating therapy.   Drug-Drug Interactions (DDIs): CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

25  All resistance variants pre-exist  Not caused by PIs, but unmasked by selective pressure  Reflect inadequate response to PEG-IFN/RBV  Predominant cause (80-90%) of incomplete viral suppression, breakthrough, or relapse  Genotype 1a > 1b Pawlotsky JM. Hepatology May; 53(5): Antiviral Resistance HCV RNA change from baseline (Log 10 IU/mL) Modest or null IFN  -ribavirin effect Study time Resistant HCV Wild-type, sensitive HCV

26  In order to reduce the development of antiviral resistance to the PIs, patients who meet futility rules indicating a high likelihood of treatment failure should discontinue therapy immediately.  Dosage reductions of boceprevir and telaprevir should not be utilized to manage treatment-related side effects.  To prevent resistance, PIs must be stopped if either PEG-IFN or RBV are discontinued.  There is no role for pre-treatment resistance testing. Myers RP et al. Can J Gastro 2012; 26(6): Antiviral Resistance: CASL Recommendations

27  Must maximize case-finding, referral, and antiviral Rx to reduce HCV burden in Canada.  Barriers to treatment (e.g. need for biopsy) should be minimized.  New therapies (boceprevir and telaprevir) markedly improve SVR rates in genotype 1 (treatment-naïve and experienced), but are complex and have additional side effects. Summary: CASL Guidelines for the Management of HCV

28 Important Hepatitis C Protease Inhibitor Drug Interactions in Mono and HIV Coinfection Alice Tseng, Pharm.D., FCSHP, AAHIVP Toronto General Hospital University of Toronto

29 Outline  Review principles of drug interactions  Understand how the pharmacology of DAAs contribute to drug interactions  Highlight important HCV drug interactions  Outline a strategy for identifying and managing drug interactions  Identify pertinent HCV drug interaction resources

30 Drug Interactions  Pharmacodynamic  Change in pharmacological effect of a drug  Additive, synergistic, or antagonistic activity or toxicity  e.g., ribavirin + AZT =  anemia  Pharmacokinetic  Change in the amount of drug(s) in body  Absorption, distribution, metabolism, elimination may be affected  Often involves CYP450 system or transporters

31 Interactions Affecting Drug Metabolism  Majority of drugs transformed to inactive forms prior to elimination through Phase I (oxidation) or Phase II (conjugation) reactions  Phase I primarily involves cytochrome P450 system  Superfamily of microsomal heme-containing enzymes  Primarily located in liver, small bowel; also kidney, lung, brain  CYP3A is the most abundantly expressed isoenzyme, is involved in the metabolism of ~50% of clinically used drugs  others: CYP2D6, 2C9, 2B6, 1A2, etc.  P-glycoprotein  Efflux membrane transporter which prevents drug accumulation in cells; has broad substrate specificity, and inhibiting or inducing the activity of this protein can lead to significant alterations in drug exposure

32 Terms DefinitionInteraction ImpactCommon Examples SubstrateAgent which is primarily cleared via a certain enzymatic pathway Rate of drug breakdown is affected by presence of enzyme inhibitors or enzyme inducers antidepressants, azoles, benzodiazepines, statins, corticosteroids, calcium channel blockers, macrolides, rifamycins, HIV PIs & NNRTIs InhibitorAgent which competes with another drug for binding at enzymatic site Decreased clearance of substrate drug; quick onset & resolution of interaction effect macrolides, azoles, HIV protease inhibitors InducerDrug that stimulates the production of additional metabolic enzymes Increased clearance of substrate drug; slower onset and resolution of interaction effect anticonvulsants, rifamycins, HIV NNRTIs, St. John’s wort

33 Boceprevir and Telaprevir Pharmacology = +++ potential for interactions with other drugs  can be clinically significant  sometimes unpredictable BoceprevirTelaprevir Dosing800 mg q8h with food750 mg q8h with food (20 g fat) SubstrateCYP3A4, P-gp, AKRCYP3A4, Pgp Inhibitor3A4, P-gp3A4, P-gp, renal transporters (?) InducerNo inducing effects in vitro (in vivo?)

34 Potential Consequences of DAA Drug Interactions  Interactions may occur in a two-way manner:  Concentrations of DAA may be altered by other drug(s)  Concentrations of concomitant drug(s) may be altered by DAA  Potential consequences include:  Increased risk of toxicity  Decreased efficacy

35 Statin Interactions  Most statins are P450 substrates  DAAs can significantly increase statin levels:  Atorvastatin: 130%  with boceprevir, 7.88-fold  with telaprevir  Pravastatin: 60%  with boceprevir   risk of toxicity, including myopathy and rhabdomyolysis BoceprevirTelaprevir Lovastatin, Simvastatin CONTRAINDICATED Atorvastatin May need to  atorvastatin dose; do not exceed >20 mg/d CONTRA- INDICATED Pravastatin Start with recommended dose and monitor for toxicity. Possible  in statin; use with caution. Rosuvastatin, Fluvastatin Possible  in statin; use with caution. [Victrelis & Incivek Product Monographs, FDA HIV/AIDS Drug Safety Communication, March 1, 2012]

36  Atorvastatin 40 mg + boceprevir:  Atorvastatin AUC  130% and Cmax  170% vs. atorvastatin alone  Suggest  atorvastatin dose with concomitant BOC; monitor for symptoms of statin toxicity if using >40 mg/d atorvastatin  Atorvastatin 20 mg + telaprevir:  Atorvastatin AUC  7.88-fold  Combination is contraindicated Atorvastatin Interactions with Boceprevir and Telaprevir Hulskotte EGJ et al. HEP DART 2011, Koloa, Hawaii, poster 122 Lee JE et al. Antimicrob Agents Chemother 2011, 55(10): Nominal time (hrs) Concentration (ng/mL) With telaprevir 25,000 30,000 20,000 15,000 10,000 5, Time (hrs) Atorvastatin concentration (pg/mL) Atorvastatin alone Atorvastatin + Boceprevir Without telaprevir

37 Effect of Steady-State Telaprevir on the Pharmacokinetics of Amlodipine 5 mg Calcium channel blockers (CCBs)  Amlodipine, diltiazem, felodipine, nifedipine, nicardapine, verapamil are CYP3A4 substrates  Concentrations may be  by boceprevir or telaprevir  Use with caution, clinical monitoring  Consider dose reduction Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):  Amlodipine AUC  179%  Monitor for dose-related toxicity Nominal time (hrs) Concentration (ng/mL) With telaprevir Without telaprevir

38 Antihypertensive Medications ClassExamplesPotential DAA Interactions ACEIEnalapril, lisinopril, ramipril (renal)Not expected ARBsLosartan (2C9>>3A4 to active metabolite) Candesartan, irbesartan (2C9) Eprosartan, olmesartan, telmisartan, valsartan (biliary) Possible  effect Low Not expected Beta- blockers Propranolol (2D6, 3A4, 2C19), carvedilol (2D6, 2C9> 1A2, 2E1, 3A4) Acebutolol, labetalol, metoprolol, pindolol (2D6) Atenolol, nadolol (renal) Possible  Low Not expected Calcium channel blockers Amlodipine, diltiazem, felodipine, nifedipine, verapamil (3A4) Risk of  CCB exposures; use with caution DiureticsHydrochlorothiazide, furosemide, spironolactone (renal) Indapamide (2C9, 2D6, 3A4) Not expected Possible 

39 Treatment of Depression in HCV Place in Therapy Examples (route of metabolism)Potential DAA Interactions First LineEscitalopram, citalopram (2C19, 3A4>>2D6) 35%  with TVR, no interaction with BOC Second LineParoxetine, fluoxetine (2D6), bupropion (2B6) Sertraline (2B6>2C9/19, 3A4, 2D6), venlafaxine (2D6>3A4), desvenlafaxine (UGT>>3A4), mirtazapine (2D6, 1A3, 3A4) Low Possible  Third LineNortriptyline (2D6) Imipramine (2D6, 1A2, 2C19, 3A>UGT) Low Possible  No EvidenceModafinil (3A4; induces 3A4) Amantadine (not metabolized) Possible  ;  DAA Not expected AvoidDuloxetine (1A2, 2D6) - CONTRAINDICATEDAdditive risk of hepatotoxicity

40 Methadone Interactions  Methadone is metabolized by CYP2B6, CYP2C19 & CYP3A, 85% protein bound; R-isomer is biologically active enantiomer  Boceprevir interaction:  In the presence of steady-state boceprevir, R-methadone AUC  16%, Cmax  10%; no clinical effects noted including opioid withdrawal  Boceprevir exposures not affected by methadone  Telaprevir interaction:  In the presence of steady-state telaprevir, R-methadone Cmin  31%, Cmax  21% and AUC  21%, but median unbound Cmin of R-methadone was similar before and during telaprevir coadministration and no withdrawal symptoms were noted  A priori methadone dose adjustments are not required when initiating DAA therapy, but close monitoring is recommended, with methadone dose adjustments if necessary Hulskotte et al. 2012, Van Heeswijk et al

41 Hormonal Contraceptives with DAAs  Hormonal contraceptives may not be as effective in women taking boceprevir or telaprevir  Boceprevir (Victrelis):  99%  AUC drospirenone, 24%  AUC EE  Use 2 alternate effective methods of contraception during treatment with BOC and Peg IFN  /RBV  Drospirenone (Yaz ®, Yasmin ®, Angelique ® ) is contraindicated  Telaprevir (Incivek):  28%  AUC, 33%  Cmin of EE  Use 2 additional non-hormonal methods of effective birth control during TVR dosing and for 2 months after the last intake of TVR.

42 Benzodiazepine Interactions  Majority are substrates of CYP3A4  Risk for prolonged/excessive sedation  Oral midazolam & triazolam are contraindicated with boceprevir and telaprevir  IV midazolam: consider  dose, close monitoring for respiratory depression or prolonged sedation  Other benzodiazepines:  dose and monitor  Consider using benzodiazepines that are glucuronidated:  Lorazepam, oxazepam, temazepam

43 Inhaled Corticosteroids  Corticosteroids are CYP3A4 substrates  Potential for  corticosteroid concentrations resulting in significantly reduced serum cortisol concentrations  Inhaled/nasal fluticasone, budesonide:  Avoid co-administration with HCV PIs if possible, particularly for extended durations.  May wish to use corticosteroid associated with less adrenal suppression (e.g., beclomethasone, ciclesonide)  Use lowest possible dose, consider non-steroidal options Victrelis & Incivek. Product Monographs, 2011

44 PDE5 Inhibitors (sildenafil, tadalafil, vardenafil)  PDE5 inhibitors are substrates of CYP3A4  Potential for DAAs to  concentrations  Dose-related side effects (headache, vasodilation, dyspepsia, visual disturbances)  Contraindicated with DAAs if using for PAH  For erectile dysfunction, use a lower dose with DAAs:  Sildenafil: 25 mg q48h, tadalafil: 10 mg q72h  Do not use vardenafil

45 Interactions Between HCV & HIV Medications  Challenges in treating HIV/HCV co-infected patients  Additive toxicities:  Anemia: ribavirin, zidovudine, DAAs  CNS: interferon, efavirenz  Potential for negative 2-way interactions   concentrations of HIV agents   concentrations of HCV DAAs

46 Antiretroviral Treatment Options for Patients on Boceprevir or Telaprevir BoceprevirTelaprevir Protease Inhibitors (PIs) Avoid with ritonavir-boosted protease inhibitors Avoid ritonavir-boosted darunavir, fosamprenavir and lopinavir Atazanavir/ritonavir OK Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Avoid efavirenz Dose  with efavirenz Etravirine (?)Etravirine OK No dataRilpivirine OK Integrase Inhibitor Raltegravir OK Maraviroc No data potential  /  maraviroc; potential benefit on fibrosis? Nucleoside Reverse Transcriptase Inhibitors Tenofovir OK Avoid AZT (anemia)

47 Managing Drug Interactions: 1) Medication Reconciliation  Ensure medication records are up to date at each visit  Prescription, OTC, vitamins/herbals, recreational drugs, inhalers, topical, prn agents  Confirm doses, prn drugs  Include all agents that have been started or stopped  Patient education:  Encourage patients to ask before taking any new prescription/non-prescription drug or supplement  Communication with other HCP!

48 Managing Drug Interactions: 2) Identify Potential Interactions  Use a systematic approach to identify combinations of potential concern  Apply knowledge of known PK characteristics  Overlapping CYP pathways, substrate, inducer, inhibitor  High index of suspicion with key classes of drugs  Utilize current drug information resources:  Product monographs, CPS, literature  Conference abstracts, specialized HCV drug interaction websites

49 Drugs Contraindicated with Boceprevir and Telaprevir (1)  1 -adrenoreceptor antagonist AlfuzosinHypotension, cardiac arrhythmia AntiarrhythmicsQuinidine, propafenone, amiodarone. Flecainide (TVR) serious/life-threatening cardiac arrhythmia AntimycobacterialsRifampinLoss of virologic response Ergot derivativesAcute ergot toxicity Herbal productSt. John’s wortLoss of virologic response StatinsLovastatin, simvastatin. Atorvastatin (TVR) Myopathy including rhabdomyolysis NeurolepticPimozideSerious/life-threatening cardiac arrhythmia Victrelis & Incivek. Product Monographs, 2011

50 Drugs Contraindicated with Boceprevir and Telaprevir (2) PDE-5 inhibitorSildenafil. tadalafil (BOC); vardenafil (TVR) Visual abnormalities, hypotension, prolonged erection, syncope Sedatives/ hypnoticsOral midazolam, triazolamIncreased sedation or respiratory depression OtherCisapride, astemizole, terfenadine Serious/life-threatening cardiac arrhythmia Anticonvulsants (BOC) Carbamazepine, phenytoin, phenobarbital Loss of virologic response OC (BOC)DrospirenoneHyperkalemia Aldosterone antagonist (TVR) EplerenoneHyperkalemia Triptans (TVR)EletriptanCoronary artery vasospasm, MI, vent. tachycardia, VF Victrelis & Incivek. Product Monographs, 2011

51 Managing Drug Interactions: Therapeutic Options  Determine clinical significance  Evaluate therapeutic options:  Alter drug dose/dosing frequency  Substitute with alternate agent  Can any drugs be permanently or temporarily discontinued while on DAA treatment?  Consider patient convenience and cost factors  Patient counselling & close monitoring is critical

52 Summary  High potential for pharmacokinetic interactions between directly acting antivirals and other drug classes  Consequences may include therapeutic failure and increased toxicity  Often, interactions can be managed, but heightened level of awareness is needed  Use a systematic approach to identify and manage individual drug regimens  Importance of a specialized, inter-disciplinary team including pharmacy

53  General  Hansten PD. Science Med 1998;  Kashuba ADM, Bertino JS Jr. Drug Interactions in Infectious Diseases, 2 nd edition, c. 2005, pp:  Metheny CJ et al. Pharmacotherapy 2001;21:  Interactions in HCV and HIV:  Kiser J et al. Hepatology 2012;55:  Tseng & Foisy. Curr Infect Dis Rep 2012;14:  Internet  Toronto General Hospital Immunodeficiency Clinic;  Liverpool Pharmacology Group;  Additional Resources

54 Side Effects of Antiviral Therapy for Hepatitis C Dr. Mark Levstik, FRCP(C) Associate Professor Medicine Division of Gastroenterology Multiorgan Transplant Unit London Health Sciences Centre

55 Side Effects with Boceprevir and Telaprevir  Hematological: (common to both PIs)  Anemia, Neutropenia  Effect is additive with INF and RBV  Gastrointestinal  Dysgeusia (BOC)  Diarrhea (TVR & ? BOC)  Anorectal irritation (TVR)  Dermatological  Telaprevir specific rash

56 Side Effect Comparison of Phase III studies Adverse EffectPeg Interferon/ RBV Boceprevir/ P/R Peg Interferon/ RBV Telaprevir/ P/R Anemia <100g/dl30%50%17%36% Rash19%17%34%56% Fatigue59%58%50%56% Diarrhoea15%20%17%26% Nausea42%46%28%39% Dysgeusia16%35%3%10% Anorectal7%29% Dysgeusia and anemia increased with boceprevir; Rash, anorectal irritation and anemia increased with telaprevir. Victrelis Product Monograph, August 2012 Incivek Product Monograph, June 2012

57 Patients  HCV genotype 1 infection  Compensated cirrhosis (Child Pugh A)  Treatment-experienced  Relapsers  Partial responders ( >2 log 10 HCV RNA decline at Week 12 but never negative)  Null responders theoretically excluded  Treated in the French early access program (From February 2011) Safety of Protease Inhibitors in Real Life: CUPIC Study Hezode C et al. EASL 2012, Abstract 8

58 Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up CUPIC: Treatment Regimen Weeks 72 SVR assessment Follow-up Peg-IFN + RBV 36 Interim analysis Hezode C et al. EASL 2012, Abstract 8 BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : mg/d BOC + Peg-IFN α-2b + RBV TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : mg/d

59 CUPIC: Patients Characteristics  Baseline patient characteristics similar between BOC and TVR  The CUPIC cohort had more advanced liver disease than in registration trials.  In BOC arm 26% would not meet RESPOND-2 inclusion criteria  In TVR arm 34% would not meet REALIZE inclusion criteria  Previous treatment response (%)BOCTVR  Partial responders4952  Relapsers4840  Null responders 3 8 Hezode C et al. EASL 2012, Abstract 8

60 CUPIC: Preliminary Safety Findings (16-Week Interim Analysis) Patients, n (% patients with ≥ 1 event) Boceprevir n=159 Telaprevir n=296 Serious adverse events (%) Premature discontinuation Due to SAEs (%) Death (%) Infection (Grade 3/4) (%) Rash Grade 3 (%) Grade 4 (SCAR) (%) Pruritus (Grade 3/4) (%) Hepatic decompensation (%) 4.4 Hezode C et al. EASL 2012, Abstract 8

61 Patients, n (% patients with ≥ 1 event) Boceprevir (n=159) Telaprevir (n=296) Anemia (%) Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8,0 g/dL) EPO use Blood transfusion Neutropenia (%) Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use Thrombopenia (%) Grade 3 ( – <50 000) Grade 4 (<25 000) Thrombopoïetin use Hezode C et al. EASL 2012, Abstract 8 CUPIC: Preliminary Safety Findings (16-Week Interim Analysis)

62 Take Home Message from CUPIC  PI therapy in patients with cirrhosis is associated with more severe and more frequent AEs  Anemia  Increased EPO use, ribavirin dose reductions and transfusions  Increased risk of severe infection  Increased risk of hepatic decompensation

63 Boceprevir Specific Side Effects  Dysgeusia and decreased appetite more prevalent than control  Hematological side effects more prevalent than control in Phase 2/3 naïve studies:  Neutropenia (<0.75 x 10 9 /L): 31% vs. 18% in controls  Platelets (< 50 x 10 9 /L): 3% vs. 1 % in controls  Anemia: 50% vs. 30% in controls  Grade II (<100 g/L): 49% vs. 29%  Grade III (<85 g/L) : 6% vs. 3%  Erythropoietin use 47% vs. 24% and pRBC 3% vs. 1% Victrelis Product Monograph, August 2012

64 Telaprevir Specific Side Effects  Rash, anorectal disorders, diarrhea and anemia more common than control  Rash seen > 50%, leads to 6% discontinuations  Mild – 37%  Moderate – 14%  Severe – 5%  Anorectal disorders seen with increase in diarrhea, itching and burning: 29% vs. 7% in controls  Anemia: 32% vs. 15% in controls  Grade II (< g/dL): 27% vs. 27%  Grade III ( g/dL) : 51% vs. 24% Incivek Product Monograph, June 2012

65 Anemia Management

66 Mechanism of RBV-Associated Anemia  RBV uptake into RBC  adenosine kinase  RBV-triphosphate  Erythrocytes lack enzymes to hydrolyze RBV phosphates  RBV-phosphates are “trapped”  Erythrocyte T 1/2 > 40 days  RBV concentration in RBC 60-fold higher than serum (60:1)  Marked depletion of RBC adenosine triphosphate (ATP)  Impairs anti-oxidant defense mechanisms  Induces RBC oxidative membrane damage  Premature extravascular RBC removal by the reticuloendothelial system De Franceschi L. Hepatology 2000; 31:

67 Ribavirin Dose Reduction vs. EPO ?  Retrospective analyses of Boceprevir phase III studies have suggested that reducing the dose of RBV did not alter the SVR rate.  In patients treated with PEG+RBV (dual therapy), the effect of RBV dose reduction ON SVR was minimal if occurring when HCV-RNA was undetectable. Sulkowski MS et al. J Hepatol 2011; 54:S Reddy KR et al. Clin Gastroenterol Hepatol 2007; 5:124-9

68 Boceprevir Anemia Management: Erythropoietin vs. Ribavirin Dose Reduction Study After completion of 4 week PEG-IFN/RBV lead-in, all patients initiated boceprevir Hemoglobin ≤100 g/L Ribavirin dose reduction (DR) n = 249 Erythropoietin (40,000 IU/wk SC) n = 251 Hemoglobin ≤ 85 g/L: Secondary Strategy (EPO, RBV DR, transfusion) EPO: erythropoietin PEG-IFN: peginterferon RBV: ribavirin Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline 687 patients treated with boceprevir RGT Poordad et al. EASL 2012, Abstract 1419 Randomisation

69 Results – Primary and Key Efficacy End Points Patients (%)  (95% CI) -0.7% (-8.6, 7.2)* End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response. *The stratum-adjusted difference (EPO vs. RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort. Poordad et al. EASL 2012, Abstract EOT ResponseSVRRelapse RBV DR EPO 205/251203/249 19/196 19/ / /251

70 Summary - Anemia Management  Ribavirin dose reduction does not decrease SVR  No advantage to Erythropoietin use, but may be used  Consider pRBC transfusion to maintain safe Hb  DAA should not be reduced  DAA should not be restarted or continued without Peg/RBV  Ribavirin may be increased once Hb recovers

71 Protease Inhibitors: Management of Anemia Hb < 100 g/L any time during treatment BoceprevirTelaprevir RBV dose reduction Up to 3 x 200 mg increments* Reduce RBV to 600 mg/day Hb > 85 g/L Maintain RBV dose reduction * Note:First dose reduction of 400mg if patient receiving 1400mg/day RBV dose reduction to 600 mg can be used with Boceprevir as wel Hb < 85 g/L EPO: 40-60,000 IU/wk AND/OR Transfusion

72 Rash Management - Telaprevir

73 Rash  Rash more prevalent in DAA but >50% with Telaprevir  Rash can be categorized:  Mild to moderate: < 30% of skin area  Moderate: 30-50% of skin area  Severe: generalized rash may progress with bullae, vesicles < 5% of patients Incivek Product Monograph, 2012

74 Rash Management Recommendations  Mild: Watchful monitoring  Oral antihistamines, moisturizers, topical steroids  Moderate: < 50% body  Monitor closely for progression/systemic symptoms  Antihistamines, moisturizers, topical steroids  Worsening/Severe: > 50% body ( < 4% of patients )  Stop telaprevir, observe closely for 7 days  IF no better, stop Ribavirin, observe for 7 days.  IF no better, stop Pegylated Interferon Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63

75 Telaprevir Severe Rash < 1%  DRESS:  Drug rash with eosinophilia and systemic symptoms  Rash, fever, facial edema ± hepatitis/nephritis  Eosinophils may not be present  Stevenson-Johnson Syndrome  Fever, target lesions and mucosal erosions/ulcers  STOP ALL drugs  Requires hospitalization  May require systemic steroids Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63

76 Other Side Effects of Boceprevir and Telaprevir

77 Gastroenterological Side Effects  Nausea, vomiting, diarrhea  Small meals three times daily with PI dosing useful  Fiber, loperamide aid with loose stool  Dysgeusia noted in Boceprevir patients  Metallic taste, rarely leads to dose reduction or discontinuation  Improved with chocolate administration

78 Gastroenterological Side Effects: Telaprevir  Nausea, vomiting and diarrhea common with TPV/PEG/RBV  Anorectal irritation:  Anorectal burning, itch and hemorrhoidal irritation common: > 29%  Therapy:  Frequent small meals, 21g fat per dose  Fiber, loperamide and topical hydrocortisone therapy, help relieve symptoms Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63

79 Management of Depression  Occurs in up to 37% of patients  Conduct pre-therapy and routine assessments with CES-D or other depression scale  Adjust interferon dose or discontinue therapy according to depression severity  May warrant use of antidepressants  Recommended agents to use with BOC and TVR: Escitalopram, citalopram (see Dr. Tseng’s chapter on DDIs)

80 Direct-Acting Antiviral Therapy: Boceprevir and Telaprevir  Patient side-effect education is important to success  Pre-therapy recommendations include:  Multivitamin, hydration, acetaminophen analgesia  Dietary recommendations to decrease GI toxicity effects ( small meals, fiber, loperamide )  Skin care through moisturizers and antihistamines  Close patient and hepatitis team communication  Monitor and pre-empt severe side effects  Drug and duration specific

81 Case Study: Treatment Naive Edward Tam MD FRCPC Medical Director LAIR Centre

82 Ms. MH  31 year old female  Diagnosed in 2004 with genotype 1a HCV  Previous IVDU  Otherwise healthy  Meds: Milk thistle  No Biopsy  ALT 1-2 x ULN on serial monitoring

83 Ms. MH  Followed periodically with monitoring of liver biochemistry  FibroScan December 9, 2010: 4.9 kPa  What evidence supports the use of Milk Thistle?  Is FibroScan a reliable and accurate tool for fibrosis assessment?  Does it represent a viable alternative to liver biopsy?

84 FibroScan versus Liver Biopsy Myers RP et al. Can J Gastroenterol Nov;24(11): Sensitivity 1-Specificity AUROC (95% CI) ≥ F2:0.74 ( ) ≥ F3:0.89 ( ) F4:0.94 ( )

85 Ms. MH  FibroScan December 9, 2010: 4.9 kPa (consistent with stage 0 – 1 fibrosis)  Discussions with patient throughout 2011 regarding therapy  Although no medical urgency, very keen to pursue therapy for personal reasons

86 Ms. MH  January 6, 2012, treatment initiated with pegylated interferon alpha-2b (120mcg) plus ribavirin (500mg BID), as planned lead-in to boceprevir-based treatment. Week 0 HCV RNA5.29 logs ALT106 Hb144 Plts295 Neutrophils6.0

87 Ms. MH: Week 4 Results Week 0Wk 2Wk 4 HCV RNA5.29 logs--Undetectable ALT Hb Plts Neutrophils Given the undetectable HCV RNA at the end of WK4 lead-in (dual therapy), is adding Boceprevir necessary?

88 Significance of Lead-in Response Vierling et al. EASL SPRINT-2: SVR based on degree of early interferon response (log decline in HCV RNA at week 4 of P/R in all patients (cohort 1 + cohort 2) < < < < < <4.0 ≥4.0 Undetectable < < < < < <4.0 ≥4.0 Undetectable < < < < < <4.0 ≥4.0 Undetectable PR48BOC RGTBOC/PR48 Log 10 viral load decrease after weeks of P/R lead-in % of patients with SVR

89 Results Through Week 12 Wk 4Wk 6Wk 8Wk 10Wk 12 HCV RNAUndetectable--Undetectable--Undetectable ALT Hb Plts Neutrophils  Boceprevir added with 5 th interferon injection  HCV RNA remains undetectable  Due to worsening anemia and fatigue, RBV dose reduced to 600mg total daily dose after wk 10 results

90 Results Through Week 24 Wk 12Wk 16Wk 20Wk 24 HCV RNAUndetectable-- Undetectable ALT Hb Plts Neutrophils  HCV RNA remained undetectable through week 24, and patient qualifies for shortened duration therapy (to D/C at week 28)

91 Case Study: Cirrhosis Nir Hilzenrat, MD Gastrointestinal Division, Department of Medicine, SMBD- Jewish General Hospital, Associate Professor of Medicine, McGill University, Montreal, Quebec

92 Case History  58 year old woman, acquired hepatitis C from blood transfusion 30 years prior  Symptoms – mild fatigue and depression  ALT 2xULN  Synthetic function normal  Viral load 3x10 5 IU/mL  Liver biopsy (2002)  F 3/4, activity 2/4

93 Case History  Previous treatment in 2000 with pegylated interferon and ribavirin  < 1 log drop at week 12  Treatment discontinued  Treatment-related side effects  Severe fatigue  Fall in Hb level (148 g/L to 108 g/L).

94 Comments Previous treatment failures classified into  Null responder  Viral load does not fall by 2 logs at week 12  Partial responder  Viral load falls by > 2 logs, but never negative  Relapser  Viral load negative on therapy but positive after therapy  Telaprevir (REALIZE study ) response in null responders was 29% (21/72)  Boceprevir (PROVIDE study) response in null responders was 40% (19/47) Zeuzem, S. et al. N Engl J Med 2011; 364: Bronowicki, JP., International Liver Congress 2012, Abstract 204, EASL 2012

95 Comments  Probability of response with F3 or F4 and prior treatment failure (48 weeks of therapy) TelaprevirBoceprevir %n%n Relapser8748/558315/18 Partial responder3411/32466/13 Null responder147/50-- Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 Vertex Pharmaceutical (Canada) Incorporated. Product Monograph: Incivek (Telaprevir tablets). (Accessed February 1, 2012)

96 Case Continued  Patient made aware of low probability of cure (15-40%)  However, she was willing to start treatment  It was accepted that we will assess the continuity of the treatment based on the response rate, i.e., HCV-RNA level, and the severity of adverse effect during the treatment  Fibroscan prior suggested cirrhosis  ALT x 4 ULN  Liver synthetic function normal  Viral load 2.8x10 6 IU/ml

97 Case Continued  Treatment was started with Peg INF/RIBA and boceprevir  At week 4 viral load decline was 0.8 logs Question  How important is the magnitude of the decline in viral load following the lead-in phase (TW4) of the PR & BOC treatment?

98 Importance of 4-Week HCV RNA in Boceprevir Triple Therapy  In RESPOND-2 likelihood of SVR for relapsers and partial-responders was associated with response to interferon in the lead-in phase SVR in all patientsSVR in F3/F4 < 1 log drop at wk 433%14-25% > 1 log drop at wk 473%55-87% Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 Bacon BR et al. N Engl J Med 2011;364:

99 Comments  In the PROVIDE study, the SVR for null responders was 40%  Week 4 HCV RNA < 1 log decline from baseline  SVR 36%  Week 4 HCV RNA >1 log decline from baseline  SVR 55% Bronowicki, JP., Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment with Boceprevir (BOC) + PR: PROVIDE Study Interim Results, International Liver Congress 2012, Abstract 204, EASL 2012

100 Case Continued  The result was discussed with the patient.  She was made aware that the likelihood of achieving SVR is poor.  However, the patient asked to reassess the probability of her success rate after 4W of PR & BOC treatment, i.e., 8W of the whole treatment.

101 Question  The HCV RNA at week 8 was undetectable  What is the likelihood of achieving SVR?

102 Question  How long should she be treated for?  At week 12 and 24 the HCV RNA remained undetectable  Usual side effects, anemia, fatigue and depression

103 Question  What are the recommended approaches for this patient (i.e. cirrhotic null responder to previous PR treatment) according to the American Association of the Study of Liver Diseases (AASLD) and Canadian Association of the Study of Liver Diseases (CASL) updated guidelines?

104 Investigational Anti-HCV Drugs Beyond Boceprevir and Telaprevir Stephen D. Shafran MD, FRCPC, FACP Professor, Division of Infectious Diseases Department of Medicine University of Alberta

105 Investigational Drugs for HCV with Activity in Humans  Direct-acting antivirals (DAAs)  Non-DAAs  Peginterferon lambda (IFN- )  Tarabivirin  Pro drug of ribavirin  Higher ratio of liver to RBC distribution than RBV  Less anemia than with RBV  Silibinin (milk thistle extract, IV formulation)  Cyclophilin inhibitors (eg. Alisporivir*) * Development on hold due to cases of pancreatitis

106 Pegylated Interferon Lambda  IFN- (a type III interferon) receptors are expressed in hepatocytes but in fewer other cells than IFN-  (a type I interferon).  In a phase-IIa trial in treatment-naïve patients, pegIFN μg weekly + RBV resulted in similar or higher virologic responses at weeks 4 and 12 vs. pegIFN  -2a + RBV with less toxicity Muir A et al. AASLD Abstract 821

107 EMERGE: PegIFN-λ/RBV vs. PegIFN  -2a/RBV PegIFN  -2a 180 μg/wk + RBV (n=133) PegIFN- 120 μg/wk + RBV (n=128) PegIFN- 180 μg/wk + RBV (n=131) PegIFN- 240 μg/wk + RBV (n=134) Treatment naïve patients with genotype 1-4 HCV infection (n=526) Wk 24: GT 2 or 3 Wk 48: GT 1 or 4 Zeuzem S et al. EASL Abstract 1360

108 EMERGE: PegIFN- /RBV vs. PegIFN  -2a/RBV: Preliminary Results to Week 12 Parameter (%) PegIFN  -2aPegIFN- 180 μg120 μg180 μg240 μg GT1/4 RVR *16.5* GT1/4 cEVR3855*56* GT 2/3 RVR314376*67* GT 2/3 cEVR Myalgia Fever29776 Hb < 10 g/dL ANC < PLT < Conjugated bilirubin Zeuzem S et al. EASL Abstract 1360 * p<0.05 compared with PegIFN  -2a

109  SVR rates comparable in pegIFN- arm vs. pegIFN  -2a  PegIFN- 180 μg dosage chosen for phase III trials EMERGE: PegIFN- /RBV vs. PegIFN  -2a/RBV: Efficacy and Safety in Genotypes 2 & 3  Fewer hematologic AEs and ALT/AST elevations with pegIFN- Zeuzem S et al. EASL Abstract 10 SVR24 (%) N = Lambda 120 µg Lambda 180 µg Lambda 240 µg Alfa 180 µg Adverse Event, % Lambda 180 µg (N = 29) Alfa 180 µg (N = 30) Hb 3.4 g/dL RBV dose reduction (Hb associated) Neutrophils < 750/mm Platelets < 100,000/mm PegIFN dose reduction (hematologic reason) ALT/AST > 5 to 10 x ULN

110 Proteins encoded by the HCV genome: Three validated targets and four classes of DAAs 5’ UTR region 3’ UTR region 9.6 kb RNA Polyprotein Polyprotein processing CE1E2p7NS2NS34ANS4BNS5ANS5B CE1E2p7NS2NS3NS4ANS5ANS5B CoreEnvelope Glycoproteins ProteaseSerine Protease Helicase RNA binding RNA-dependent RNA polymerase NS4B Serine Protease Cofactor Adapted from Asselah T et al. Liver International 2011; 31 Suppl 1:68-77 NS5B polymerase inhibitors Nucleoside analogsNon-nucleoside analogs 3 34 NS5A inhibitors 2 2 NS3-4A protease inhibitors 1 1

111 HCV NS3/NS4A Protease Inhibitors (1)  Inhibit cleavage of viral polyprotein chain, essential to HCV replication.  Very active against genotype (GT) 1.  A single nucleotide mutation in the NS3 region (R155K) results in resistance in GT 1a, but two mutations are required for resistance in GT 1b.  Some have activity against non-1 genotypes, but very little clinical data exist.  “First generation” NS3 PIs (boceprevir and telaprevir) are linear ketoamides and are associated with anemia;  “Second generation” NS3 PIs are macrocyclic and are not associated with anemia.

112 HCV NS3/NS4A Protease Inhibitors (2)  The two most developed after BOC/TVR are simeprevir (TMC-435) 1 and faldaprevir (BI ) 2. Both are in fully enrolled phase 3 clinical trials vs. dual PegIFN + RBV controls; results are expected in early  Simeprevir and faldaprevir are dosed once daily (150 and 120 mg, respectively) and do not produce additive anemia beyond PegIFN + RBV.  Simeprevir is associated with some increase in bilirubin due to reversible inhibition of OATP1B1 and MRP2 transporters.  Faldaprevir inhibits glucuronyl transferase and can cause a Gilbert’s like syndrome (similar to the HIV protease inhibitor, atazanavir).  Faldaprevir is also associated with rash and photosensitivity. 1. Fried MW et al. AASLD Abstract LB-5 2. Sulkowski M et al. EASL Abstracts 60 and 66

113 HCV NS3/NS4A Protease Inhibitors (3)  Two NS3 PIs (danoprevir 1 and ABT ) are being developed for administration with low dose ritonavir.  Ritonavir, an HIV protease inhibitor, is a potent inhibitor of CYP3A4; ritonavir increases exposure of drugs metabolized principally via CYP3A4.  Other NS3 PIs are under development, including asunaprevir (BMS ), MK-5172, GS-9451, sovaprevir (ACH-1625), whereas the development of several others has been terminated. 1. Rouzier R et al. EASL Abstract Lawitz E et al. EASL Abstract 1220

114 HCV NS5A Inhibitors 1. Gao M et al. Nature 2010; 465: Pol S et al. Lancet Infect Dis 2012; 12(9):671-7  NS5A is a protein with no known enzymatic function, but a definite, yet poorly defined role in viral replication.  NS5A inhibitors are very potent and pangenotypic in the replicon system 1. They are significantly more active vs. genotype 1b than genotype 1a.  Daclatasvir, the most developed NS5A inhibitor, is given once daily, and is in phase 3 in treatment naïve patients with genotypes 1 and 4, and in phase 2 for genotypes 2 and 3, and for genotype 1 in the HIV co-infected.  NS5A inhibitors in phase 2 are ABT-267 and GS-5885  NS5A inhibitors have no “signature” toxicity to date 2.

115 Antiviral Activity of Daclatasvir in Combination with PegIFN  2a + RBV in Treatment of Naïve Patients with Chronic HCV Genotype 1 Infection Placebo + PegIFN  -2a 180 µg/wk + RBV 1000/1200 mg/d Daclatasvir 10 mg QD + PegIFN  -2a 180 µg/wk + RBV 1000/1200 mg/d Daclatasvir 60 mg QD + PegIFN  -2a 180 µg/wk + RBV 1000/1200 mg/d Treatment naïve HCV GT1 patients n=48 Pol S et al. Lancet Infect Dis 2012; 12(9):671-7 Daclatasvir 3 mg QD + PegIFN  -2a 180 µg/wk + RBV 1000/1200 mg/d Day 1Week 48 Week 72 SVR 24

116 Daclatasvir (DCV) with PegIFN  -2a + RBV: Virologic Response at Weeks 4, 12 & SVR (ITT) Percent HCV RNA negative (<10 IU/mL by Roche TaqMan) RVRcEVR PRPR + DCV 3 mgPR + DCV 10 mg SVR (24) PR + DCV 60 mg Pol S et al. Lancet Infect Dis 2012; 12(9): patients per treatment arm; the 60 mg QD dose was selected for phase 3

117 HCV NS5B Polymerase Inhibitors  NS5B is a RNA-dependent RNA polymerase, responsible for viral RNA synthesis  The viral polymerase is the “classic” target for antiviral drugs (eg. DNA-dependent DNA polymerase in HSV and VZV or RNA-dependent DNA polymerase [reverse transcriptase] in HIV and HBV)  As with HIV RT inhibitors, there are two subtypes of NS5B inhibitors,  Nucleoside/nucleotide analogues  Act as RNA chain terminators  High barrier to resistance  Pan-genotypic  Non-nucleoside inhibitors  Least potent class of DAA  Low barrier to resistance

118 HCV NS5B Polymerase Inhibitors: Drugs with Antiviral Activity in Humans  Nucleoside/nucleotide analogues  Mericitabine (RG-7128)  Sofosbuvir (GS-7977/ PSI-7977)  VX-135 (ALS-2200)  Non-nucleoside inhibitors  Tegobuvir (GS-9190)  Setrobuvir (ANA-598)  ABT-333 (lead Abbott NNI)  ABT-072 (back-up Abbott NNI)  VX-222  BI

119 IFN-Free, All Oral Regimens with SVR Data  As of October 2012, 5 pharmaceutical companies have presented pilot data demonstrating that SVR can be achieved in small numbers of patients.  The majority of IFN-free regimens to date continue to include ribavirin.  Only one study to date has included patients with cirrhosis (SOUND C-2).  The most common combination of agents in IFN-free regimens for genotype 1 has been a 3-drug combination of a NS3 PI, a NS5B non-nucleoside (NN) inhibitor and ribavirin.  For GT 2 & 3, IFN-free regimens demonstrating SVR are sofosbuvir with either RBV or daclatasvir.

120 IFN Free SVR: The Very First Report (Daclatasvir + Asunaprevir in GT1 Prior Null Responders) Lok AS et al. EASL 2011; NEJM 2012;366:  SVR was achieved in 2/9 GT 1a and 2/2 GT 1b prior null responders to PR with 24 weeks of DCV + ASV (all enrolled patients were non-cirrhotic)  On therapy breakthrough was common in GT 1a PT4PT8 PT12PT24 PT36PT48 HCV RNA (log 10 IU/mL) Week LLOQ LLOD Follow-upDaclatasvir+asunaprevir

121 Dual Oral Therapy with Daclatasvir and Asunaprevir x 24 Weeks for HCV GT1b Virologic Response (%) Prior Null Responders (n=21) [6 IL-28B CC] IFN Ineligible/Intolerant (n=22) [16 IL-28B CC] Week 4 RVR5286 Week 12 cEVR91 EOTR9186 SVR Suzuki F, et al. EASL Abstract 14  Study conducted in Japan  All had genotype 1b  Treated with asunaprevir (NS3 PI) and daclatasvir (NS5A inhibitor) x 24 weeks

122 PILOT: NS3 PI + NN + RBV: Virologic Responses  n = 11, HCV GT1, treatment-naïve, non-cirrhotic; 8 GT1a, 3 GT 1b  Only IL-28B CC patients were enrolled, so that they would have a high probability of salvage with PegIFN + RBV in the event that all-oral therapy failed  All were treated with ABT-450/r 150/100 mg QD + ABT mg QD + RBV 1000/1200 mg/d Lawitz E, et al. EASL Abstract 13 Wk 4 (RVR) Wk 12 (EOT) SVR12 SVR24 HCV RNA Negative (%) SVR36 11/11 10/11 9/11 n/N

123 CO-PILOT: NS3 PI + NN + RBV: Virologic Responses  Because of the favorable results in PILOT, CO-PILOT was open to all IL-28B genotypes and explored prior PR non-responders;  All had genotype 1 and were non-cirrhotic  In CO-PILOT, a different NS5B non-nucleoside inhibitor was used (ABT-333) than in PILOT (ABT-072) Poordad F et al. EASL Abstract 1399 HCV RNA negative (%) ABT-450/r 250/100 mg QD + ABT RBV Treatment naive (n = 19; 17 G1a, 2 G1b) ABT-450/r 150/100 mg QD + ABT RBV Treatment naive (n = 14; 11 G1a, 3 G1b) ABT-450/r 150/100 mg QD + ABT RBV Prior PR Non-responders* (n = 17; 16 G1a; 1 G1b) RVR eRVR SVR4 SVR * 11 partial responders, 6 null responders

124 INFORM-SVR: NS3 PI + Nucleoside + RBV in GT1: SVR12 by HCV Subtype and IL28B Genotype  Data shown are patients treated with 24 weeks of mericitabine + danoprevir/r + ribavirin; all were treatment naïve and non-cirrhotic  SVR12 rates were encouraging in GT1b but disappointing in GT1a Gane E et al. EASL Abstract 1412 SVR12 (%) Overall CCNon-CC IL28B Genotype n/N = All (n = 64) GT1a (n = 43) GT1b (n = 21) 26/6411/4315/216/194/152/420/457/2813/ n/N =

125 68 SOUND-C2: NS3 PI + NN ± RBV: SVR12 by Study Arm  N=362; the largest IFN-free study to date  All had GT1 and were treatment naïve; 10% had cirrhosis  All received faldaprevir 120 mg QD + RBV 1000/1200 mg/d  Patients were randomized to 5 arms, 4 containing BI , 600 mg TID (3 arms) or 600 mg BID (one arm) for 3 different durations  RBV-free arm was stopped prematurely due to high relapse rate Zeuzem S et al. EASL Abstract 101 SVR12 (%) BID 28 wks + RBV TID 28 wks (no RBV) TID 40 wks + RBV TID 28 wks + RBV TID 16 wks + RBV BI Dosing 48/81 49/80 43/7753/7818/46 n/N

126 SOUND-C2 BID Dosing Arm: Higher SVR12 in Patients With GT1b or GT1a-IL28B CC  Boehringer Ingelheim has decided to undertake additional studies of this 3-drug regimen only in patients with GT1b and those with GT1a who are IL-28B CC Zeuzem S et al. EASL Abstract 101 SVR12 (%) n/N = a non-CC 1a CC 1b non-CC 1b CC SVR According to IL28B and HCV Subtype: BID 28 Wks + RBV (ITT) /226/831/379/11 HCV Subtype and IL28B Genotype

127 Sofosbuvir (GS-7977) Gane E et al. EASL Abstract 1113  Nucleotide NS5B inhibitor  Once daily oral dosing with no food effect  No described toxicity to date  Pangenotypic  No virological breakthroughs reported to date  Studied in combination with RBV or daclatasvir or simeprevir*  In GT2 & 3, sofosbuvir + RBV x 12 weeks achieved SVR24 in 10/10 patients; sofosbuvir + RBV x 8 weeks achieved SVR12 in 10/10 patients (all non cirrhotic)  Two phase 3 RCTs are fully enrolled in GT2 & 3 (including cirrhotics); results expected EASL 2013  FISSION: Treatment naïve patients randomized to sofosbuvir + RBV x 12 weeks vs. PegIFN + RBV x 24 weeks  FUSION: Treatment failure patients randomized to 12 wk vs. 16 wk of sofosbuvir + RBV * No data have been presented on sofosbuvir + simeprevir

128 Sofosbuvir + RBV x 12 Weeks: Results in GT1 Treatment Naïve Patients 1. Gane E et al. EASL Abstract Gilead Press Release, Apr 19, 2012  In ELECTRON, 25/25 achieved EOT; 22/25 (88%) achieved SVR4 and 3/25 (12%) relapsed 1  In QUANTUM, 17/17 achieved EOT; 10/17 (59%) achieved SVR4, and 7/10 (41%) relapsed 2  Combined ELECTRON and QUANTUM SVR in GT1 naives is 32/42 (76%)  Only non-cirrhotic patients were enrolled in ELECTRON and QUANTUM  Future studies in GT1 will examine  Longer treatment durations of Sofosbuvir + RBV  The addition of a third antiviral drug

129 The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease. For more information visit or call This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc. The Canadian Liver Foundation gratefully acknowledges the participating health care professionals for their contributions to this project and for their commitment to the liver health of Canadians.

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