Hepatitis C Nonresponders

Prakash Zacharias

Proportion of Genotypes in India

Hissar

et al (N

)

Singh

et al (N

)

Panigr

ahi e

t al (N

)

Amarapurka

r et a

l(W)

Chaudhuri e

t al (E

)

Chaudhury

et al(E

)

Raghuram

an et a

l (S&E)

Veliammai

(S)

Khaja et a

l (S)

PVS0%

10%20%30%40%50%60%70%80%90%

100%

MixedOther GenotypesGenotype3Genotype2Genotype1

Modified from Mukhopadhya A; J. Biosci.2008, 33 465–473

Genotypes & Duration of therapy

Genotype I,4,5,6

Genotype 2, 3

48weeks

24weeks

SVR

SVRVirologic ‘‘cure’’Improves morbidity and mortality

Evolution of Hepatitis C Treatment

IFN α 2b x 24 wks

IFN α 2b x 48 wks

IFN α 2b x tiw + Ribavirin

PEG IFN

PEG IFN QW + Ribavirin

PEG IFN QW + wt based Ribavirin

0%

18%

41%

24-36%

54%

61%

Treatment Response

SVR on Treatment on PEG IFN + Ribavirin therapy

Series10

10

20

30

40

50

60

70

80

90

Geno 2,3Geno I

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 RNAreplication & virion assembly

Boceprevir (BOC) and Telaprevir(TVR)

Non Responders

Null ResponderNo decline (by at

least 2 log) in HCV RNA wk12

RelapserHCV RNA undetectable

during treatment; Reappear after stopping

At least 2 log IU/ml at wk 12; Detectable wk 24

Partial Responder

Boceprevir in previously treated cases- RESPOND-2 Trial

Overall Relapser Partial responder0

10

20

30

40

50

60

70

80

66

75

52

59

69

40

21

29

7

BOC/PR48BOC RGTSOC

Bacon BR et al; N Engl J Med 2011;364: 1207-1217.

Boceprevir in previously treated cases- RESPOND-2 Trial

Overall Relapser Partial responder0

10

20

30

40

50

60

70

80

66

75

52

59

69

40

21

29

7

BOC/PR48BOC RGTSOC

Bacon BR et al; N Engl J Med 2011;364: 1207-1217.

4-wk lead-in phase of PegIFN +RBV → fixed duration triple therapyx 44wks

Boceprevir in previously treated cases- RESPOND-2 Trial

Overall Relapser Partial responder0

10

20

30

40

50

60

70

80

66

75

52

59

69

40

21

29

7

BOC/PR48BOC RGTSOC

Bacon BR et al; N Engl J Med 2011;364: 1207-1217.

4-wk lead-in phase → RGT (BOC +PegIFN + RBV x32 wks; If detectable HCV RNA wk 8, SOC for additional 12 weeks

Boceprevir in previously treated cases- RESPOND-2 Trial

Overall Relapser Partial responder0

10

20

30

40

50

60

70

80

66

75

52

59

69

40

21

29

7

BOC/PR48BOC RGTSOC

Bacon BR et al; N Engl J Med 2011;364: 1207-1217.

Teleprevir in previously treated cases (REALIZE study)

Overall Relapser Partial Responder Null Responder0

10

20

30

40

50

60

70

80

90

100

64

83

59

29

66

88

54

33

17

24

15

5

T12PR48L1-T12PR48SOC

Zeuzem S et al.N Engl J Med 2011;364: 2417-2428

Teleprevir in previously treated cases (REALIZE study)

Overall Relapser Partial Responder Null Responder0

10

20

30

40

50

60

70

80

90

100

64

83

59

29

66

88

54

33

17

24

15

5

T12PR48L1-T12PR48SOC

Zeuzem S et al.N Engl J Med 2011;364: 2417-2428

Triple therapy x 12 wks → SOC x

36 wks

Teleprevir in previously treated cases (REALIZE study)

Overall Relapser Partial Responder Null Responder0

10

20

30

40

50

60

70

80

90

100

64

83

59

29

66

88

54

33

17

24

15

5

T12PR48L1-T12PR48SOC

Zeuzem S et al.N Engl J Med 2011;364: 2417-2428

Lead-in treatment with

SOC x 4 weeks → triple therapy x

12 wks

Teleprevir in previously treated cases (REALIZE study)

Overall Relapser Partial Responder Null Responder0

10

20

30

40

50

60

70

80

90

100

64

83

59

29

66

88

54

33

17

24

15

5

T12PR48L1-T12PR48SOC

Zeuzem S et al.N Engl J Med 2011;364: 2417-2428

Recommendation

Virological relapse or Partial responders

( Evidence - Class 1,Level A)

GHANY ET AL.,HEPATOLOGY, October 2011

Re-treatment with Boceprevir or Telaprevir,+ PEG IFN alfa and weight-basedribavirin

Recommendation

Virological relapse or Partial responders

( Evidence - Class 1,Level A)

GHANY ET AL.,HEPATOLOGY, October 2011

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)

Recommendation

GHANY ET AL.,HEPATOLOGY, October 2011

Evidence Class 2b, Level B

Re-treatment with telaprevir + PEG IFN alfa +

wt based ribavirin

Null Responder

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

THANKS

IL28B Testing & SVR in Gen 1 (SOC)

Caucasians Blacks0

10

20

30

40

50

60

70

80

69

48

33

15

27

13

CCCTTT

Thompson AJ et al. Gastroenterology 2010;139:120-129.