1. How to optimize treatment of G1 patients? Prof. G. K. K. Lau 2012

2. Standard of care (SOC) for chronic HCV infection –Peginterferon (PegIFN) + ribavirin (RBV) –48 weeks (HCV G1, 4, 5 and 6) –24 weeks (HCV G2 and 3) Induce sustained virologic response (SVR) rates (associated with long-term clearance of HCV infection) –40-50% (G1) –>80% (G2 and 3) Two major advances –Direct-acting antiviral (DAA) agents –Single-nucleotide polymorphisms Prof. G. K. K. Lau 2012 Introduction

3. Five distinct drug classes currently under development The only drugs approved by FDA at present –Inhibitors of the HCV non-structural protein 3/4A (NS3/4A) serine protease –Inhibits HCV replication and virion assembly Boceprevir (BOC) Telaprevir (TVR) –Monotherapy: rapid development of drug resistance –Combination therapies (with PegIFN and RBV) lower drug resistance and improves antiviral response. Prof. G. K. K. Lau 2012 DAA Agents

4. BOC /TVR in combination with PegIFN-α and RBV have shown great improvement on SVR compared to SOC For Treatment Naïve Patients –Four weeks lead-in treatment, PegIFN-α and RBV only; BOC 800 mg (with food), 3 times/day with PegIFN-α and RBV (24-44 weeks) –TVR 750 mg (with food), 3 times/day with PegIFN-α and RBV (12 weeks) + 12-36 weeks of PegIFN and RBV Prof. G. K. K. Lau 2012 Optimal treatment for CHC G1 (Naïve Patients)

5. Patients without cirrhosis (BOC/PegIFN/RBV treated) –HCV RNA undetectable at weeks 8 and 24 –Shortened duration of treatment (28 weeks: 4 weeks lead- in + 24 weeks of combination therapy) Patients without cirrhosis (TVR/PegIFN/RBV treated) –HCV RNA undetectable at weeks 4 and 12 –Shortened duration of treatment (24 weeks) Patients with cirrhosis –48 weeks therapy regardless of drug use (BOC/TVR + PegIFN + RBV) Prof. G. K. K. Lau 2012 Optimal treatment for CHC G1 (Naïve Patients)

6. Treatment termination (patients without cirrhosis) –HCV RNA level >100 IU/mL at week 12 or detectable at week 24 Treatment termination (patients with cirrhosis) –HCV RNA level >1000 IU/mL at week 4 or 12 and/or detectable at week 24 Prof. G. K. K. Lau 2012 Optimal treatment for CHC G1 (Naïve Patients)

7. Virological relapse / partial responders after a prior course of treatment with PegIFN-α and/or RBV  Re-treatment with BOC/TVR + PegIFN-α and/or RBV Re-treatment with TVR/PegIFN-α /RBV for prior null responders to standard PegIFN-α/RBV therapy Response-guided therapy using BOC/TVR based treatments cannot be recommended for null responder Prof. G. K. K. Lau 2012 Optimal treatment for CHC G1 (Patients Previously Received Therapy)

8. Treatment termination (BOC/PegIFN alfa/RBV) –HCV RNA level >100 IU/mL at week 12 –High chance of antiviral resistance development Treatment termination (TVR/PegIFN alfa/RBV) –HCV RNA level >1000 IU/mL at week 4 or 12 –High chance of antiviral resistance development Prof. G. K. K. Lau 2012 Optimal treatment for CHC G1 (Patients Previously Received Therapy)

9. IL28B genotype –Pretreatment predictor of SVR to PegIFN alfa, RBV and protease inhibitor therapy (CHC G1) –Testing for additional information on possible treatment response or probable treatment duration needed Prof. G. K. K. Lau 2012 Role of IL28B Testing

10. Adverse events, e.g. Anemia –Should reduce RBV dose / terminate treatment Virological breakthrough (>1 log increase in serum HCV RNA above nadir) –Protease inhibitors therapy should be discontinued Drug-Drug interactions (affects pharmacokinetic parameters) Patients who: Fail to have virological response/Experience virological breakthrough/Relapse on protease inhibitor –Should not receive re-treatment with other protease inhibitor TVR and BOC are not recommended for patients under 18 years of age (safety and efficacy concerns) Prof. G. K. K. Lau 2012 Other complications

11. BOC and TVR are promising agents for improved SVR in CHC G1 patients BOC/TVR + PegIFN-α/RBV combination therapies have shown great improvement on SVR compared to SOC Many complex treatment issues remain to be solved Further phase 2 and 3 testing required –Asian –Genotype/subtype Prof. G. K. K. Lau 2012 Closing Remarks