Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto

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 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 900 Cirrhosis 800 700 600 Decomp 500 Modelled incidence 400 HCC 300 Transplant 200 100 0 1967 1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022 2027 Year Remis et al. PHAC 2007

6. Antiviral Therapy Must be Maximizedto Make an Impact  80% SVR rate 60% SVR rate 40% SVR rate 100 90 34% ↓ 80 70 68% ↓ Liver-related death vs. no treatment (%) 60 50 40 30 20 0 Current* 25% 50% 75% 100% Proportion of population treated * Assumes 30% Dx & up to 25% Rx’d in 2010. Outcomes at 2020. Davis GL et al. Gastroenterology 2010; 138(2):513-21

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 Pre-Treatment Assessment: Is Liver Biopsy Really Necessary? Bedossa P et al. Hepatology 2003; 38(6):1449-57

11. 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 ≤ 10-15 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. Interleukin 28B (IL28B) • 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 100 P=1.06x10-25 P=2.06x10-3 P=4.39x10-3 P=1.37x10-28 80 Numbers on bars represent n 60 SVR (%) 40 20 102 433 336 70 91 30 14 35 26 186 559 392 0 T/T T/C C/C T/C C/C T/C C/C T/C C/C European-Americans African-Americans Hispanics Combined rs12979860 SVR (%) Non-SVR (%) Ge. Nature 2009. Suppiah. Nat Genet 2009. Tanaka. Nat Genet 2009. Thomas. Nature 2009.

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. Futility Rules Indicate Treatment FailureEven if the Viral Load Has Declined 107 1,800,000 106 99.9% reduction: Continue? 105 104 1,230 HCV RNA (IU/mL) 475 103 102 If futility rules met, RNA is rising! Stop therapy! 10 1 W0 W1 W2 W3 W4 Slide courtesy of Dr. J. Feld.

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 Drug-Drug Interactions (DDIs) * Minor elimination pathways include P-glycoprotein and aldoketoreductase.

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. http://www.hep-druginteractions.org/ http://medicine.iupui.edu/clinpharm/ddis/ 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 Antiviral Resistance Modest or null IFNa-ribavirin effect 1 0 -1 HCV RNA change from baseline (Log10 IU/mL) -2 Resistant HCV -3 -4 Wild-type, sensitive HCV -5 Study time Pawlotsky JM. Hepatology. 2011 May; 53(5):1742-51

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. Antiviral Resistance:CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

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 andHIV 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 maybe 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

33. Boceprevir and Telaprevir Pharmacology = +++ potential for interactions with other drugs • can be clinically significant • sometimes unpredictable

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 [Victrelis & Incivek Product Monographs, 2011. FDA HIV/AIDS Drug Safety Communication, March 1, 2012]

36. Atorvastatin 40 mg + boceprevir: Atorvastatin AUC  130% andCmax  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 30,000 100 25,000 Atorvastatin alone Atorvastatin + Boceprevir 10.0 20,000 With telaprevir 1.00 Concentration (ng/mL) Atorvastatin concentration (pg/mL) 15,000 Without telaprevir 10,000 0.10 5,000 0 0.01 0 8 16 24 32 40 48 0 10 20 30 40 50 Time (hrs) Nominal time (hrs) Hulskotte EGJ et al. HEP DART 2011, Koloa, Hawaii, poster 122 Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

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 5.00 With telaprevir 0.50 Concentration (ng/mL) Without telaprevir 0.05 0.01 0 50 100 150 200 250 Nominal time (hrs) • Amlodipine AUC  179% • Monitor for dose-related toxicity Lee JE et al. Antimicrob Agents Chemother 2011, 55(10):4569-74

38. Antihypertensive Medications

39. Treatment of Depression in HCV

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 ofR-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. 2011.

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

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) Victrelis & Incivek. Product Monographs, 2011

50. Drugs Contraindicated with Boceprevir and Telaprevir (2) Victrelis & Incivek. Product Monographs, 2011