Hepatitis C Nonresponders Prakash Zacharias

Hep C in Northern India Chakravarti et al., Indian J Med Res 133, March 2011, pp 326-331

Proportion of Genotypes in India Modified from Mukhopadhya A; J. Biosci.2008, 33 465–473

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

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

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%

SVR on Treatment on PEG IFN + Ribavirin therapy

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

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

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

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

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

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: 1207-1217.

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: 1207-1217.

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: 1207-1217.

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: 1207-1217.

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: 2417-2428

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: 2417-2428

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: 2417-2428

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: 2417-2428

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

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

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

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

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IL28B Testing & SVR in Gen 1 (SOC) Thompson AJ et al. Gastroenterology 2010;139:120-129.