1. Hepatitis C Nonresponders
Prakash Zacharias

2. Hep C in Northern India
Chakravarti et al., Indian J Med Res 133, March 2011, pp

3. Proportion of Genotypes in India
Modified from Mukhopadhya A; J. Biosci.2008, –473

4. Genotypes & Duration of therapy
48weeks
Genotype I,4,5,6
24weeks
Genotype 2, 3

5. SVR
Virologic ‘‘cure’’
Improves morbidity and mortality
SVR

6. Evolution of Hepatitis C Treatment
Response
IFN α 2b x 24 wks 0%
IFN α 2b x 48 wks
18%
IFN α 2b x tiw + Ribavirin
41%
PEG IFN
24-36%
PEG IFN QW + Ribavirin
54%
PEG IFN QW + wt based Ribavirin
61%

7. SVR on Treatment on PEG IFN + Ribavirin therapy

8. Question
HCV Genotype I with advanced fibrosis – PEG IFN + Ribavirin non responder -> What next ?

9. Developments in HCV treatment
Direct-acting antiviral (DAA) agents
Identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection

10. HCV NS3/4A serine protease required for RNA
replication & virion assembly
Boceprevir (BOC) and Telaprevir
(TVR)

11. AASLD Recommendations
The optimal therapy for genotype 1, chronic HCV infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A).
GHANY ET AL.,HEPATOLOGY, October 2011

12. HCV RNA undetectable during treatment; Reappear after stopping
Non Responders
Relapser
HCV RNA undetectable during treatment; Reappear after stopping
Null Responder
No decline (by at least 2 log) in HCV RNA wk12
At least 2 log IU/ml at wk 12; Detectable wk 24
Partial Responder

13. Boceprevir in previously treated cases- RESPOND-2 Trial
The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7- 9 hours);The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours)
The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy
Bacon BR et al; N Engl J Med 2011;364:

14. Boceprevir in previously treated cases- RESPOND-2 Trial
4-wk lead-in phase of PegIFN +RBV → fixed duration triple therapyx 44wks
The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7- 9 hours);The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours)
The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy
Bacon BR et al; N Engl J Med 2011;364:

15. Boceprevir in previously treated cases- RESPOND-2 Trial
4-wk lead-in phase → RGT (BOC +PegIFN + RBV x32 wks; If detectable HCV RNA wk 8, SOC for additional 12 weeks
The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7- 9 hours);The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours)
The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy
Bacon BR et al; N Engl J Med 2011;364:

16. Boceprevir in previously treated cases- RESPOND-2 Trial
The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7- 9 hours);The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours)
The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy
Bacon BR et al; N Engl J Med 2011;364:

17. Teleprevir in previously treated cases (REALIZE study)
The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment for 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks.
Zeuzem S et al.N Engl J Med 2011;364:

18. Teleprevir in previously treated cases (REALIZE study)
Triple therapy x 12 wks → SOC x 36 wks
The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment for 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks.
Zeuzem S et al.N Engl J Med 2011;364:

19. Teleprevir in previously treated cases (REALIZE study)
Lead-in treatment with SOC x 4 weeks → triple therapy x 12 wks
The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment for 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks.
Zeuzem S et al.N Engl J Med 2011;364:

20. Teleprevir in previously treated cases (REALIZE study)
The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment for 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks.
Zeuzem S et al.N Engl J Med 2011;364:

21. Recommendation Virological relapse or Partial responders
Re-treatment with Boceprevir or Telaprevir,
+ PEG IFN alfa and weight-based
ribavirin
Virological relapse or Partial responders
( Evidence - Class 1,Level A)
GHANY ET AL.,HEPATOLOGY, October 2011

22. Recommendation Virological relapse or Partial responders
Response-guided therapy using either a boceprevir- or telaprevir-
based regimen for relapsers
(Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir),
& partial responders
(Class 2b, Level B for boceprevir; Class 3, Level C for telaprevir)
Virological relapse or Partial responders
( Evidence - Class 1,Level A)
GHANY ET AL.,HEPATOLOGY, October 2011

23. Re-treatment with telaprevir + PEG IFN alfa + wt based ribavirin
Recommendation
Re-treatment with telaprevir + PEG IFN alfa + wt based ribavirin
Null Responder
Evidence Class 2b, Level B
GHANY ET AL.,HEPATOLOGY, October 2011

24. Recommendation
Treatment should be withdrawn because of the high likelihood of developing antiviral resistance
Patients re-treated with telaprevir + PEG IFN + Ribavirin who continue to have detectable HCV RNA > 1,000 IU at weeks 4 or 12

25. Thanks

26. IL28B Testing & SVR in Gen 1 (SOC)
Thompson AJ et al. Gastroenterology 2010;139: