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How to optimize treatment of G1 patients?

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

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How to optimize treatment of G1 patients?

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

  2. Introduction • 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

  3. DAA Agents • 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

  4. Optimal treatment for CHC G1(Naïve Patients) • 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

  5. Optimal treatment for CHC G1(Naïve Patients) • 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

  6. Optimal treatment for CHC G1(Naïve Patients) • 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

  7. Optimal treatment for CHC G1(Patients Previously Received Therapy) • 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

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

  9. Role of IL28B Testing • IL28B genotype • Pretreatment predictor of SVR to PegIFNalfa, 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

  10. Other complications • 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

  11. Closing Remarks • 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

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