1. R2. 임형석 / Pf. 김병호

2. I NTRODUCTION Chronic hepatitis C infection 130~150 million worldwide 7 genotypes genotype 1 predominates(about 70% in USA): most difficult to cure Subtype 1b: most prevalent genotype overall east Asia Treatment history 1957: Interferon -> ‘interfere with viral replication’ 1998: Rebetron(Intron A + Ribavirin) 2001: PEG-Intron + Ribavirin -> poorly tolerable 2003: Intron A + Rebetol(oral ribavirin) for pediatrics

3. I NTRODUCTION Treatment history 2007: Telaprevir(HCV protease inhibitor) 2011: FDA approved Boceprevir + Telaprevir in combination with pegylated interferon and ribavirin 2012: many clinical trials with combination Direct Acting Antivirals 2013: FDA approved Simeprevir, Sofosbuvir + PEG-IFN + ribavirin -> lower rates in nonresponders to peg-IFN a + ribavirin 2014: phase 3 studies of interferon-free therapies of various drug combinations have been completed

4. I NTRODUCTION

6. M ETHODS Study design Multinational(18 countries, 116 sites), phase 3, multicohort study including in North and South America, Europe, and Asia between May 11, 2012, and Oct 9, 2013 Eligible patients aged at least 18 years genotype 1b infection HCV RNA ≥ of 10 000 IU/mL one of three cohorts: treatment-naive, previous non-responder to peginterferon alfa plus ribavirin, ineligible for or intolerant of peginterferon alfa plus ribavirin Exclusion criteria Decompensated liver function

7. M ETHODS Placebo Daclatasvir 60mg qd + Asunaprevir 100mg bid 1.2.3.

8. M ETHODS Primary efficacy endpoints SVR 12 (sustained virological response) treatment-naive and non- responders Secondary efficacy endpoints SVR 12 rates in ineligible, intolerant, or ineligible & intolerant SVR 12 by: IL28B genotype, HCV RNA < 25 IU/mL undetectable at 12wk, HCV RNA < 25 IU/mL, detectable or undetectable, and less than 25 IU/mL undetectable at weeks 1, 2, 4, 6, 8, 12, and both 4 and 12; at end of treatment; and at post-treatment week 24 Virological breakthrough post-treatment relapse Safety endpoints: incidence of adverse events, serious adverse events, discontinuations because of adverse events

9. R ESULT S

11. no differences in SVR12 : sex, age, race, BMI, IL28B genotype Overall SVR12 rates were similar : with or without cirrhosis SVR12 rates were similar : null and partial responders

12. R ESULT S only HCV RNA of 800 000 IU/mL or greater and presence of NS5A resistance-associated variants (at positions L31 or Y93) as negative predictors of SVR12.

13. R ESULT S Daclatasvir + asunaprevir was well tolerated among ineligible / intolerant / ineligible & intolerant

14. C ONSLUSION In this global phase3 study in genotype 1b including a high proportion with cirrhosis Interferon & ribavirin free all-oral dual therapy with daclatasvir plus asunaprevir  Provided SVR rates of 82–91% at post-treatment week 12 or later Cirrhosis was associated with decreased SVR rates with peginterferon alfa + ribavirin alone or in combination with telaprevir, boceprevir, simeprevir, sofosbuvir In our study, response was similar in patients with or without cirrhosis

15. C ONSLUSION Daclatasvir plus asunaprevir showed reduced hematological toxicities and systemic adverse events compared with peginterferon alfa plus ribavirin-based therapies daclatasvir + asunaprevir is a treatment option favourable safety and drug interaction profile high response rates good tolerability with more comorbidities especially when genotype 1b is highly prevalent