1. R1 Jin Suk Kim/ Prof. Jae Jun Shim
Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection
Ira M. Jacobson, M.D., John G. McHutchison, M.D., Geoffrey Dusheiko, M.D., Adrian M. Di Bisceglie, M.D.,
K. Rajender Reddy, M.D., Natalie H. Bzowej, M.D.,Patrick Marcellin, M.D., Andrew J. Muir, M.D., Peter Ferenci, M.D.,
Robert Flisiak, M.D., Jacob George, M.D., Mario Rizzetto, M.D., Daniel Shouval, M.D., Ricard Sola, M.D.,
Ruben A. Terg, M.D., Eric M. Yoshida, M.D., Nathalie Adda, M.D., Leif Bengtsson, B.Sc., Abdul J. Sankoh, Ph.D., Tara L. Kieffer, Ph.D.,Shelley George, M.D., Robert S. Kauffman, M.D., Ph.D., and Stefan Zeuzem M.D.,
for the ADVANCE Study Team*
N ENG J MED ;25 :
R1 Jin Suk Kim/ Prof. Jae Jun Shim

2. Introduction Chronic HCV infection
Hepatic fibrosis & cirrhosis, Portal hypertension, Hepatic failure, Hepatocellular carcinoma
Pegylated interferon + Ribavirin at least 48weeks
Virologic response 40~50% ( in Genotype 1, no previous Tx.)
 This study (phase 3 trials)
: To evaluate the efficacy and safety of telaprevir-based therapy
: Administered in a regimen that was guided by the patient’s response
: Among no previous treatment for HCV infection.
Telaprevir (peptidomimetic HCV NS3/4A serine protease inhibitor)  In Phase 2 trials, telaprevir + pegylated interferon + Ribavirin : Improved efficacy : Potential for shortening the duration of treatment
1. Chronic HCV infection are at risk for progressive hepatic fibrosis, cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma
2. For the past decade, treatment with pegylated interferon and ribavirin has been associated with rates of sustained virologic response
of 40 to 50%
3. In phase 2 trials, telaprevir in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment

3. Methods - patients & study design
- International, Phase 3, Randomized, Double-blind trial Placebo-controlled for telaprevir patients with HCV genotype 1 infection who had not received previous treatment
Eligible criteria
Exclude criteria
- 18~70years of age
- HCV genotype 1 infection (confirmed by liver biopsy within 1yr)
- Compensated liver cirrhosis
- HBsAg(-), HIV Ab(-)
- ANC≥ 1,500 PLT≥ 90,000
- Hb ≥12(female), ≥13(male)
- Decompensated liver disease
- Liver disease from other causes
- Hepatocellular carcinoma

4. Methods – patients & study designPR
(control)
Placebo + Peginterferon + Rivabirin
Peginterferon + Rivabirin
f/u
Peginterferon + Rivabirin
f/u
Undetectable HCV RNA at weeks 4 and 12
Telaprevir + Peginterferon + Rivabirin
T12PR
Peginterferon + rivabirin
Peginterferon + Rivabirin
f/u
Detectable HCV RNA either at week 4 or at week 12
Placebo+
Peginterferon + Rivabirin
Telaprevir + Peginterferon + Rivabirin
T8PR
4weeks
12weeks
24weeks
48weeks
72weeks
Telaprevir : orally, 750mg q 8hrs
Peginterferon : subcutaneous injection 180ug /week
Ribavirin : orally 1000mg /day(<75kg), 1200mg/day(≥75kg)

5. Methods - Efficacy & safety assessments
Efficacy  Plasma HCV RNA levels
- Use of the COBAS TaqMan HCV RNA assay, version 2.0 (Roche)
- Measured on
: day 1 & 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 36, 40, 48 wks
: f/u visits 4 weeks after the end of treatment
: 60 and 72 wks
Safety
- Chemical & hematologic assessments
: at the same time as the efficacy assessement during the treatment
: at 4 weeks after the last dose of the study drug was administered

6. Methods - Evaluation of HCV sequence, End points
- Primary endpoint
: proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment
- Secondary endpoint
: proportion of patients with undetectable HCV RNA at week 72; at week 4, week 12, or both weeks 4 and 12; at the end of treatment; and 12 weeks after the last planned dose of treatment.
- Relapse
: undetectable HCV RNA levels at the end of the treatment period but had confirmed detectable HCV RNA levels sometime between the end of treatment and 24 weeks after the last study dose

7. Results - Sutdy patients
Study patients
Figure 1. Randomization and Sustained Virologic Response in Study Patients.
1088 patients
P<0.001

8. Results - Sutdy patients
1. Patients were well balanced with respect to major baseline demographic and disease characteristics
Table 1.
Baseline Characteristics of the Study Patients, According to Treatment Group

9. Results - Efficacy Rapid virologic response
Extended rapid virologic response
A total of 73% of patients in the T12PR group, 67% in the T8PR group, and 44% in the PR group had undetectable HCV RNA 72 weeks after starting treatment (P<0.001)
2. 68%, 66%, and 9% in the three groups, respectively, had undetectable HCV RNA at week4 (rapid virologic response); and 58%, 57%, and 8% in the three groups, respectively, had undetectable HCV RNA at weeks 4 and 12 (extended rapid virologic response).
3. Among patients who had undetectable HCV RNA levels after the last dose of study treatment, relapse occurred in 9% in the T12PR group, 9% in the T8PR group, and 28% in the PR group.
P<0.001
Table 2. Response during and after the Treatment Period, According to Treatment Group

10. Results - Efficacy
Analyses of subgroups according to various characteristics showed thatthere were higher rates of sustained virologic response with telaprevir than with peginterferon–ribavirin alone
2. Sustained virologic response occurred in 71% of the patients with HCV genotype 1a and 79% with genotype
1b in the T12PR group, in 66% and 74% of the patients with genotype 1a and genotype 1b, respectively,
in the T8PR group, and in 41% and 48% in of the patients with genotype 1a and genotype 1b, respectively, in the PR group
Figure 2. Difference in Rates of Sustained Virologic Response (SVR) between the T12PR and Control Groups,
According to Subgroups

11. Results
Safety
The incidence of gastrointestinal disorders (nausea and diarrhea), pruritus, rash, and anemia was at least 10 percentage points higher in either of the telaprevir groups than in the PR group
Table 3. Incidence of Serious Adverse Events and Most Common Adverse Events, According to Treatment Group

12. Peginterferon + Rivabirin Telaprevir + Peginterferon
Conclusions
Peginterferon + Rivabirin
significantly improved rates
of sustained virologic response with only 24weeks
( in patients with HCV genotype 1 infection, had no previous Tx.) ∧
significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients.
Telaprevir + Peginterferon
+ Rivabirin