1. Preparing for Direct Acting Antivirals (DAAs) in PracticeNew Paradigms in the Management of HCV Sherilyn C. Brinkley, MSN, CRNP Nurse Practitioner/Program Manager Infectious Disease Department Johns Hopkins University Baltimore, Maryland

2. HCV Genotype 1 Peginterferon, weekly Ribavirin, weight-based, daily Boceprevir or telaprevir, thrice daily Duration variable based on regimen used and on-treatment viral kinetics HCV Genotypes 2 and 3 1 Peginterferon, weekly Ribavirin, 800 mg, daily Duration 24 weeks HCV Genotypes 4 1 Peginterferon, weekly Ribavirin, weight-based, daily Duration 48 weeks HCV Standard of Care 2011 Ghany MG, et al. Hepatology. 2009;49:1335-1374.

3. Preparing for Anti-HCV Therapy

4. Case StudyCarmen Carmen is a 59-year-old female from Puerto Rico diagnosed with chronic HCV in 1999 after moving to the United States and starting job as medical assistant –Previously evaluated and treated by a gastroenterologist but fell out of care in 2004 –Reports taking peginterferon and ribavirin for 48 weeks leading to an undetectable viral load followed by relapse She heard about new anti-HCV drugs with shorter duration and wants more information

5. Who Is a Candidate for Anti-HCV Treatment with DAAs? Adults with chronic HCV genotype-1 infection Treatment-naive or prior relapsers or nonresponders If cirrhotic, should be compensated Ability to adhere to dosing (peginterferon, ribavirin, and protease inhibitor) and monitoring schedule The protease inhibitor is never used as monotherapy Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

6. Who Is NOT a Treatment Candidate? Contraindications to peginterferon/ribavirin apply Planning for pregnancy or unwilling to use adequate contraception Coadministration of contraindicated drugs –Highly dependent on CYP3A for clearance –Strongly induce CYP3A Special populations where safety and efficacy not established –Organ transplant –End-stage liver disease –Coinfected with HIV or HBV –Pediatrics Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

7. What Are Key Components of HCV Evaluation? Basic lab tests –HCV RNA by PCR, genotype, complete metabolic panel, prothrombin time/international normalized ratio, thyroid stimulating hormone, pregnancy test Liver histology assessment (as needed) –Liver biopsy –Fibrosis markers Comorbid disease status Gauge patient motivation to take anti-HCV therapy

8. Carmens Laboratory Findings TestResultReference Range Hemoglobin (g/dL)13.112–16.0 g/dL Platelets (/mm 3 )160,000150,000–400,000 ALT (U/L) 88ALT (U/L) Bilirubin, total (mg/dL)0.7<1.0 Albumin (g/dL)4.23.5–5.5 Creatinine (mg/dL)1.10.6–1.2 International Normalized Ratio1.01.0–1.2 HCV RNA1.8 x 10 9 IU/mL HCV genotype1a Body mass index29 Liver biopsyMetavir grade 2 inflammation Stage 3 bridging fibrosis

9. Carmens Comorbidities and Current Medications Comorbidities –Hypertension –Coronary artery disease –Hyperlipidemia –Insomnia Current medications –Simvastatin –Aspirin –Trazodone –Atenolol

10. How Do You Prepare Patients for Therapy? Educate about treatment regimens and potential side effects Discuss adherence to medications, administration schedule, food requirements, monitoring schedule Explain variable treatment durations and futility rules Review current medications, herbal products, and supplements for drug interactions Counsel regarding pregnancy risk and contraception

11. How Do You Prepare Your Practice Setting for Integration of DAAs? Ensure adequate appointment time for patient counseling Limit number of patients starting treatment each week to avoid clinic volume overload Use treatment initiation checklist Use pocket guides for drug interactions, response-guided therapy, and futility rules Delegate tasks to others when appropriate –Prior authorizations –Medication administration teaching –Specialty pharmacy services

12. Carmens Follow-Up Appointment Carmen presents to clinic to review labs and biopsy results Decision is made to treat with peginterferon, ribavirin, and a protease inhibitor Next steps –Discuss side effects and lessons learned from prior therapy –Review current medication list for drug-drug interactions and discuss plan for changes –Consult patients cardiologist regarding clearance for treatment and an alternative lipid-lowering agent

13. Treatment Goals and Challenges

14. Why Treat Chronic HCV? Sustained virologic response (SVR) is achievable SVR is associated with gradual regression of fibrosis SVR is associated with lower risk of liver failure and hepatocellular carcinoma Pearlman BL, et al. Clin Infect Dis. 2011;52:889-900.

15. What Are the Benefits of Using DAAs? Higher SVR rates observed across all patient groups 1-4 –Previously untreated, relapsers, partial and null responders Response-guided therapy allows for 24- or 28-week duration for most treatment- naive patients with rapid response 5,6 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 3. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 4. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 5. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 6. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

16. Boceprevir SPRINT-2 1 Naive RESPOND-2 2 Nonresponders 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2. 5. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Protease Inhibitor Phase III Clinical Trials Telaprevir ADVANCE 3 Naive ILLUMINATE 4 Naive REALIZE 5 Nonresponders

17. SPRINT-2Boceprevir in Treatment-Naive Genotype-1 Patients Abbreviations: B, boceprevir 800 mg TID; P, peginterferon -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; TW, treatment week. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Two cohorts: 1, nonblack; 2, black.

18. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. SPRINT-2SVR by Cohort and Treatment Arm

19. RESPOND-2Boceprevir in Genotype-1 Prior Nonresponders Abbreviations: B, boceprevir 800 mg TID; P, peginterferon -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy; TW, treatment week. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

20. RESPOND-2SVR by Prior Response Abbreviations: B, boceprevir 800 mg TID; P, peginterferon -2b 1.5 µg/kg/wk; R, ribavirin 600–1400 mg/d; RGT, response-guided therapy. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

21. ADVANCETelaprevir in Treatment-Naive Genotype-1 Patients Abbreviations: eRVR, extended rapid virologic response (undetectable HCV RNA at weeks 4 and 12); P, peginterferon -2a 180 µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

22. ADVANCESVR Rates Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416

23. REALIZETelaprevir in Genotype-1 Prior Nonresponders Abbreviations: P, peginterferon -2a 180 µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

24. REALIZESVR by Prior Response Abbreviations: LI, lead-in; P, peginterferon -2a 180 µg/wk; R, ribavirin 1000–1200 mg/d; T, telaprevir 750 mg q8h. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

25. What Are the Challenges of Triple Combination Therapy? Increased complexity –Protease inhibitor dosed every 8 hours –Food requirements –High pill burden More adverse effects Frequent lab monitoring and clinic visits Emergence of resistance-associated variants if SVR not achieved Increased cost

26. Using Response-Guided Therapy

27. How Does Response-Guided Therapy Impact Treatment Duration? Both boceprevir and telaprevir use a response-guided therapy approach Allows on-treatment virologic response to dictate treatment duration among noncirrhotics Early response is the goal and may allow for a shorter duration of therapy

28. BoceprevirResponse-Guided Therapy HCV RNA Results Treatment-Naive Patients Previous Partial Responders and Relapsers Undetectable HCV RNA at weeks 8 and 24 Complete triple therapy at week 28 Complete triple therapy at week 36 Detectable HCV RNA at week 8 Continue triple therapy through week 36, then administer peginterferon/ribavirin only through week 48 For all patients: peginterferon/ribavirin only weeks 1 through 4, then add boceprevir Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

29. BoceprevirAdditional Duration Instruction Response-guided therapy was not studied in patients who did not achieve early virologic response (<2-log drop in HCV RNA by week 12) during prior therapy –These patients should receive 4 weeks of peginterferon/ribavirin followed by 44 weeks of triple therapy For treatment-naive patients who have a poor response (<1-log drop in HCV RNA) to peginterferon/ribavirin after the 4-week lead-in phase, consider extending boceprevir in combination with peginterferon/ribavirin through week 48 Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

30. TelaprevirResponse-Guided Therapy HCV RNA Results Treatment-Naive Patients and Prior Relapsers Prior Partial and Null Responders Undetectable HCV RNA at weeks 4 and 12 Continue triple therapy through week 12, then administer peginterferon/ribavirin only through week 24 Continue triple therapy through week 12, then administer peginterferon/ribavirin only through week 48 Detectable HCV RNA at weeks 4 and/or 12 Continue triple therapy through week 12, then administer peginterferon/ribavirin only through week 48 For all patients: telaprevir, peginterferon, and ribavirin start on day 1 Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

31. Should Response-Guided Therapy Be Used in Cirrhotics? Boceprevir 1 –Patients with compensated cirrhosis should receive 4 weeks of peginterferon alfa and ribavirin followed by 44 weeks of triple therapy Telaprevir 2 –Treatment-naive patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 of telaprevir combination treatment may benefit from an additional 36 weeks of peginterferon/ribavirin (48 weeks total) 1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 2. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

32. What If a Patient Has a Poor Virologic Response? Futility (stopping) rules are guidelines that require discontinuation of treatment medications at specific time points in the event of inadequate response Stopping rules for futility –Decrease drug exposure –Minimize emergence of resistance –Lower cost

33. BoceprevirFutility (Stopping) Rules WeekHCV RNA Result Action 12100 IU/mLStop all 3 medications 24DetectableStop all 3 medications Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.

34. TelaprevirFutility (Stopping) Rules WeekHCV RNA Result Action 4>1000 IU/mLStop all 3 medications 12>1000 IU/mLStop all 3 medications 24DetectableStop peginterferon/ribavirin (telaprevir already stopped at week 12) Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

35. What Are the Implications of Inadequate Virologic Response? HCV has rapid viral dynamics and high mutation rate 1 Baseline resistance mutations exist –7% of population in boceprevir trials 2 –5% of population in telaprevir trials 3 –Some achieve SVR regardless 2,3 Majority of patients with protease inhibitor treatment failure are left with resistant variants 2,3 Predominant strain returns to wild type in majority within 2 years 4,5 Cross resistance with other protease inhibitors anticipated 1 Long-term clinical impact unknown 1. Kieffer TL, et al. J Antimicrob Chemother. 2010;65:202-212. 2. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 3. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011. 4. Vierling JM, et al. 46th EASL; April 14-18, 2010; Berlin, Germany. Abstract 2016. 5. Sullivan JC, et al. 47th EASL; March 30-April 3, 2011; Barcelona, Spain. Abstract 8.

36. Safety Considerations with DAAs

37. Are There Drugs to Avoid with Protease Inhibitors? Boceprevir and telaprevir are inhibitors of CYP3A 1,2 Use of boceprevir or telaprevir with drugs/herbs metabolized by CYP3A may lead to 1,2 –Altered drug concentrations –Loss of therapeutic activity –Adverse events from toxicity Refer to lists of contraindicated drugs and drugs to use with caution in FDA-approved product package inserts 1,2 Use drug-drug interaction pocket guide and refer to drug interaction websites –http://www.hep-druginteractions.org/ Review patient medication/supplement list at each patient interaction 1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 2. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

38. Are There Additional Contraceptive Requirements with DAAs? Ribavirin may cause birth defects and fetal death Negative pregnancy test prior to therapy and monthly 2 forms of contraception during therapy and for 6 months posttherapy –Systemic hormonal contraception should not be relied upon as effective method during protease inhibitor use Decreased ethinyl estradiol concentrations –Use 2 effective nonhormonal methods of contraception (barrier methods or nonhormonal IUD) Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

39. What Are the Most Common Side Effects with Protease Inhibitors? Boceprevir (35% of subjects) 1 –Fatigue, anemia, nausea, headache, dysgeusia Telaprevir (5% higher than in controls) 2 –Rash, pruritus, anemia, nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue, vomiting, anal pruritus 1. Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. 2. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

40. Anemia Management Is a Mainstay of Anti-HCV Therapy Increased anemia with boceprevir and telaprevir Hematologic parameters at baseline and treatment weeks 2, 4, 8, 12, and periodically after–typically every 4 weeks–or more frequently as clinically indicated Utilize anemia management tools employed with peginterferon and ribavirin –Ribavirin dose reduction –Erythropoietin –Never dose reduce protease inhibitor Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011. Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.

41. Adherence Equals Safety Adherence with medication regimen is critical but only part of the story Adherence with… Medication regimen Lab schedule Clinic appointment schedule Drug interactions schedule Contraception

42. Carmens Pretreatment Counseling Select medication dosing schedule every 79 hours for protease inhibitor Customize written daily schedule for taking ribavirin and protease inhibitor with detailed food requirements Reinforce adherence with doses, labs, and clinic visits Instruct to not take new medications, supplements, or herbals without provider clearance Emphasize to never discontinue or dose reduce the protease inhibitor Review side effects of protease inhibitor, peginterferon, and ribavirin

43. Carmens Pretreatment Counseling Discuss and document contraceptive plan –Postmenopausal –Vasectomy Review response-guided therapy and potential treatment durations Explain rationale for futility rules Review clinic/provider contact information Provide lab requisitions, lab schedule, next appointment reminder Demonstrate peginterferon injection

44. Carmen Begins Triple Therapy She leaves with lab orders for end of treatment weeks 2 and 4 She has a follow-up visit scheduled in 2 weeks She will begin treatment the next day after breakfast –1 st telaprevir and ribavirin doses at 7:00 am –1st peginterferon dose planned for 6:00 pm She remembers the flu-like symptoms with peginterferon from prior therapy and plans to premedicate with ibuprofen She will enlist the support of her family

45. Summary DAAs improve SVR rates among all genotype-1 patient groups Triple therapy utilizes response-guided therapy and potential for shortened treatment duration Anti-HCV treatment is increasingly complex with drug-drug interactions, increased pill burden and dosing frequency, risk of protease inhibitor resistance, and more side effects Pretreatment education requires adequate time and detail to prepare patients for treatment success

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