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

How to optimize treatment of G1 patients?

Prof. G. K. K. Lau 2012

• 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


Introduction

• 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.


DAA Agents

• 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


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)



• 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



• 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


Optimal treatment for CHC G1(Patients Previously Received Therapy)

• 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


Optimal treatment for CHC G1(Patients Previously Received Therapy)

• 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


Role of IL28B Testing

• 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)


Other complications

• 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


Closing Remarks

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

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