1. HCV: Treat now or Defer Todd Wills, MD ETAC Infectious Disease Specialist HEPATITIS C TREATMENT EXPANSION INITIATIVE MULTISITE CONFERENCE CALL JUNE 19, 2013 Excerpted and adapted from: Seizing the Opportunity: Optimizing Today’s HCV Therapies, Exploring Their Role in Tomorrow’s Paradigm – Clinical Care Options - Hepatitis

2. Why Treat Chronic Hepatitis C? The disease – Common, chronic, and potentially progressive – Complications are becoming more common [1,2] Liver failure, HCC The treatment – Viral cure, or SVR, is achievable – SVR associated with histologic improvement and gradual regression of fibrosis [3] – SVR reduces risk for liver failure and HCC, improves survival [4,5] 1. Kanwal F, et al. Gastroenterology. 2011;140:1182-1188. 2. Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5:365-370. 3. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 4. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 5. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.

3. We Understand the Rules of the Game With IFN-Based Treatment Establishing patient candidacy Assessing potential drug–drug interactions Evaluating likelihood of SVR in treatment- naive and treatment-experienced patients Applying response-guided treatment algorithms to maximize response and mitigate treatment failure Optimally managing adverse events

4. For Genotype 2 or 3, PegIFN/RBV Remains Standard of Care Highly effective therapy with higher cure rates than genotype 1 24 wks of therapy is recommended [1,2] – Some patients (with RVR and low baseline HCV RNA) may be treated for 16 wks if therapy poorly tolerated, although relapse rates may be higher [2] Future regimens may offer further improvements 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264.

5. Rationale for Prompt Treatment of HCV HCV is a progressive disease, associated with persistence of viral replication and ongoing necroinflammation and fibrosis Remission (SVR) is associated with loss of active viral replication and improvement in hepatic fibrosis Important questions – Does that equate to a need to treat all patients? – Can we avoid losing time for patients destined to progress? – How do we avoid unnecessary or detrimental treatment when there are improved treatments pending?

6. Indications for Treatment of Chronic HCV Infection All patients, regardless of the degree of fibrosis, are potential candidates for treatment Patients with mild disease may not require immediate treatment For those who require treatment – Patients should be fit for the regimen – Patients should have the ability to adhere to treatment goals and monitoring

7. Pts Who Want Tx  Want to be cured of disease  Personal or social reasons  Plans for pregnancy  Social support  Eligible for reimbursement now Pts Who Are Eligible for Tx  Eligible for pegIFN/ RBV  Fit for regimen  No contraindications  Disease stage Pts Who Are Motivated and Understand...  Likelihood of response  Risks/benefits of treatment  Risk of resistance  Possibility of shortened therapy  What is “coming down the line” for their genotype Who Should Be Treated Now?

8. Severity of Disease Increases Need for HCV Therapy but Also Impairs Response  May not need immediate treatment  BUT  Easier to treat  High likelihood of response Advanced disease/ cirrhosis Mild disease  Greater need for treatment  BUT  Response may be impaired  Perhaps more effective options in future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria

9. What Are My Chances of Being Cured With Current Therapy?  Black  Cirrhosis  Genotype 1 (1a worse than 1b)  IFN nonresponsive  IL28B TT Favorable prognostic factors Less favorable prognostic factors  White  No fibrosis  Genotype 2/3  IFN responsive (eg, RVR/EVR or response to lead-in)  Previous relapser  IL28B CC

10. Limitations of Current Regimens and Prospects for Future Regimens Current Must be eligible for pegIFN/ RBV Large pill burden, TID dosing of PIs (at present); parenteral IFN Challenging adverse events High likelihood of resistance with treatment failure Current PIs only effective for genotype 1 Possibility of resistance with poor adherence Future Perhaps IFN free Lower pill burden, less than TID dosing; perhaps all oral May be better tolerated May not generate resistance Pangenotypic or at least more Higher barrier to resistance with some classes

11. Challenging Patients for Whom Treatment With Current Options Less Than Optimal Cirrhosis (all genotypes) Decompensated cirrhosis Null responders Pretransplantation Posttransplantation Renal failure – Impaired renal function – Dialysis – Renal transplantation recipients Injection-drug users – Methadone substitution Thalassemics Children IFN contraindicated IFN intolerant Those on “edge” of society Psychiatric comorbidity

12. The Need to Cure Cirrhosis: Survival in Patients With HCV and Cirrhosis Fattovich G, et al. Gastroenterology. 1997;112:463-472. Compensated After first major complication Survival Probability 100 Patients (%) 80 60 40 20 0 12001224364860728496108 Mos 384 65 Pts at Risk, n 376 39 342 21 288 11 236 7 165 4 126 4 79 3 52 3 39 2 25 1

13. The First-Generation Protease Inhibitors: Where Are We Now? Telaprevir and boceprevir are harbingers of important treatment advance Improved SVR rates in both naive and experienced patients Certain patients (advanced disease) require therapy imminently and should be treated now Others may be motivated to be treated now—opportunities for cure, candidates for shortened therapy, and/or personal reasons For many, the choice is not clear The advent of triple therapy changes the way treatment discussed with patients – Clinicians must educate and advocate for patients to choose the correct course of treatment