Clinical Cases Hepatitis C Naïve Patients

Rafael Esteban Liver Unit.

Hospital General Universitari Vall Hebron. Barcelona.

• 27 year old woman, • Diagnosed with Chronic Hepatitis C 3 years ago • Never treated • Risk factor: occasional IVDU 10 years ago • Weight: 65 kg • No comorbidity, no medications • Genotype 1b, HCV RNA 1.000.000 UI/mL

• Fibroscan: 8 KPa

Case study 1

Case study 1

• Asymptomatic

• She wants to clear the viral infection quickly before being pregnant, so she wants to start a treatment rapidly

• No contraindication for the treatment

Would you treat her?

• No, because she has no significant fibrosis

• Yes, because she is really motivated

Would you perform an IL28B genotyping in this patient ?

• Yes, because the IL28B polymorphism can

influence the treatment strategy • No

Impact of IL28B polymorphisms on SVR in naïve patients

RVS

(%)

PR48

50/64 n/N=

CC TT

BOC44/ PR48

44/55

CT

BOC RGT

63/77

PR48

33/116

BOC44/ PR48

82/115

BOC RGT

67/103

PR48

10/37

BOC RGT

23/42

78 82 80

28

65 71

27

55 59

0

20

40

60

80

100

BOC44/ PR48

26/44

RVS

(%)

PR48

35/55 n/N=

CC TT

T12PR

45/50

PR48

6/26

T12PR

16/22

PR48

20/80

T12PR

48/68

CT

64

90

25

71

23

73

0

20

40

60

80

100

Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

RVS

(%)

PR48

50/64 n/N=

CC TT

BOC44/ PR48

44/55

CT

BOC RGT

63/77

PR48

33/116

BOC44/ PR48

82/115

BOC RGT

67/103

PR48

10/37

BOC RGT

23/42

78 82 80

28

65 71

27

55 59

0

20

40

60

80

100

BOC44/ PR48

26/44

RVS

(%)

PR48

35/55 n/N=

CC TT

T12PR

45/50

PR48

6/26

T12PR

16/22

PR48

20/80

T12PR

48/68

CT

64

90

25

71

23

73

0

20

40

60

80

100

Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542

≈89 % of CC patients treated with BOC/PR

were eligible for shorter therapy

Impact of IL28B polymorphisms on SVR in naïve patient

≈80 % of CC patients treated with TVR/PR

were eligible for shorter therapy

Case study 1

• IL28B genotyping: CC

Are you going to treat her?

• PegInterferon +Ribavirin

• PegInterferon +Ribavirin+Telaprevir

• PegInterferon+Ribavirinin + Boceprevir

SVR Rates by First Time to PCR Negativity in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx.

PEG-IFN α-2b 1.5 µg/kg QW + ribavirin 800-1400 mg/day

89%

25%17%

0%

20%

40%

60%

80%

100%

% o

f Pat

ient

s

4, (n=110) 12, (n=61) 24, (n=24)

85%93%

67%

0%

20%

40%

60%

80%

100%

% o

f Pat

ient

s4, (n=13) 12, (n=15) 24, (n=3)

1. S. Zeuzem et al., Journal of Hepatology 44 (2006) 97–103. 2. Manns M. et al., Lancet 2001; 358: 958–65.

24 Weeks Tx.1, N=235 48 Weeks Historical Control2, N=38

47% HCV RNA PCR Negative (<29IU/mL at Week 4.

Standard of Care for Genotype 1 Treatment-Naive Patients

BOC + PegIFN + RBV

48 0 28 12 4

PegIFN + RBV PegIFN + RBV

8 36

BOC + PegIFN + RBV

24

Early response*; stop at Wk 28; f/u 24 wks

F/u 24 wks

Boceprevir[1,2]

TVR + PegIFN + RBV

48 0 24 12 4

eRVR†; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u

24 wks

Telaprevir[2,3]

1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.

*Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy). †Undetectable HCV RNA at Wks 4 and 12 of triple therapy.

No eRVR; PegIFN + RBV

Case study 1

• IL28B genotyping: CC • Day 1: start of antiviral therapy

– Peginterferon α-2a 180 ug/week – Ribavirin: 400 mg BID – Telaprevir 750 mg every 8 hours

• Week 4:

– Side effect: fatigue Hb decline to 11 g/dl – Bad Tolerance to High fat- food every 8 h – HCV RNA undetectable

72,8 74,3

0

20

40

60

80

100

OPTIMIZE: Efficacy of Telaprevir BID vs

Telaprevir q8h in GT1 HCV Infection Primary endpoint: SVR12

SVR1

2 (%

)

270/371 274/369

T12(q8h)/PR T12(bid)/PR

T12(bid)/PR was non-inferior to T12(q8h)/PR for SVR12 Difference (95% CI): 1.5% (–4.9%, 12%)

Buti M, et al. AASLD 2012. Abstract LB-8.

Case study 1

• Week 4 – Therapy adjusted – Peginterferon α-2a 180 ug/week – Ribavirin: 400 mg BID – Telaprevir bid

• Week 8

– Better tolerance and compliance – Minimal Rash in arms

Case study 1

• Week 10 – Rash increases arms and thorax (Moderate rash-

Grade 2) – HCV-RNA undetectable

Management of mild rash: which antihistamine?

OK to use with HCV PIs

Chlorpheniramine

Desloratidine

Levocetirizine

Promethazine

http://www.hep-druginteractions.org

In this patient, desloratidine was initiated

Case study 1

• Week 10 – Rash increased arms and thorax (Moderate rash-

Grade 2) – Topic steroids and desloratidine was initiated – Anemia stable – HCV-RNA undetectable

• Week 11

– No improvement in rash – Telaprevir was stopped

Drug considerations: mild and moderate rash

Treating patients with mild or moderate rash Use topical corticosteroids* Permitted systemic antihistaminic drugs may be tried for the treatment of associated

pruritus Limit exposure to sun/heat and wear loose-fitting clothes

Rash

Mild

Moderate

Telaprevir discontinuation is generally NOT required

Telaprevir discontinuation is generally NOT required

For moderate rash that progresses, permanent discontinuation (do not dose-reduce) of telaprevir should be considered

If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted.

Peginterferon alfa may be continued unless interruption is medically indicated

*Concomitant use of systemic dexamethasone with telaprevir may result in loss of therapeutic effect of telaprevir. This combination should be used with caution or alternatives should be considered Telaprevir EU SmPC

Case study 1 • Week 10

– Rash increased arms and thorax (Moderate rash-Grade 2) – Topic steroids and desloratidine was initiated – Anemia stable – HCV-RNA undetectable

• Week 11

– No improvement in rash – Telaprevir was stopped

• Week 12

– No Changes in rash – All the drugs were stopped – HCV RNA undetectable

What are the chances to get an SVR?

• 40%

• 60%

• > 90%

20

PROVE2 (telaprevir): study design

T12P12 (n=78) (no RBV)

PR48 (n=82)

T12PR12 (n=82)

0 Weeks

24 48 12 36

TVR + Peg-IFN

Peg-IFN + RBV Placebo

+ Peg-IFN + RBV

TVR + Peg-IFN +

RBV

Peg-IFN + RBV

TVR + Peg-IFN

+ RBV

T12PR24 (n=81)

Hézode C, et al. N Engl J Med 2009;360:1839–50

• Phase IIb, randomized, placebo-controlled, partially double-blind trial in 323 treatment-naïve patients with chronic HCV genotype 1 infection

PR: peginterferon/ribavirin; Peg-IFN: peginterferon alfa-2a; RBV: ribavirin; TVR: telaprevir; HCV: hepatitis C virus

46 36

60 69

PROVE2 (telaprevir): overall SVR Rates

PR48 T12P12 (no RBV)

T12PR12 T12PR24

100

80

60

40

20

0

Hézode C, et al. N Engl J Med 2009;360:1839–50

38/82 28/78 49/82 56/81

Patie

nts w

ith S

VR (%

)

SVR: sustained virologic response

SVR according to the treatment and IL28B genotype (telaprevir PROVE2 post-hoc analysis)

100 94

75 64

44

67

18

31 20

33 25

0

20

40

60

80

100

T12PR12 T12PR24 T12P12 PR48

CC CT TT

12 12

12 27

1 5

12 18

15 16

1 3

3 4

4 22

0 3

7 11

5 16

1 4

Prop

ortio

n of

pat

ient

s (%

)

Bronowicki J-P, et al. J Hepatol 2012;56 (Suppl 2):S430–1

Case study 1

• Follow-up 24-week • HCV RNA: undetectable.

24

Summary

• Naïve patients infected with HCV genotype 1 Easy to treat patients • IL28B CC, • Caucasian/White • Non-cirrhotic

• Can be cure with 12 weeks of triple combination

treatment with telaprevir, peginterferon, and ribavirin

Case Study 2

• 54 year old man, lawyer

• IVDU sporadically 20 years ago

• Chronic Hepatitis C diagnosed 6 years ago

• HCV genotype 1 b,

• F3

• Friends with HCV treated and non responders

• He was afraid about his disease

• He would like to be treated with DAAs but he was also afraid

about therapy!!!!!!

26

Case study 2

• He started – Peginterferon α-2b 1.5 ug/kg/week – Ribavirin: 600 mg BID

• Week 4:

– Side effect: fatigue – Viral load: 4.2 log10 (vs 6.1 log10 at D1)

Lead-in Predicts SVR

28

SVR

(%)

187 228

121 234

178 218

BOC RGT BOC/PR48 PR48

21 73

3 62

31 79

16 24

12 26

22 36

BOC RGT BOC/PR48 PR48

6 24

0 21

5 16

Non-Black Patients Black Patients

≥1 log 10 HCV RNA decline from baseline <1 log 10 HCV RNA decline from baseline

Poordad F. N Engl J Med. 2011; 364:1195-1206.

Case study 2

• Started boceprevir 800 mg/8h at Week 4.

• Week 8. – Side effects: ↑ fatigue, dysgeusia, no rash. – Hb: 10.5 g/dL (vs 13 g/dL at Day 1). – HCV RNA: undetectable.

29

SVR for Early and Late Viral Responders With Boceprevir

30

ADVANCE

Poordad F. N Engl J Med. 2011; 364:1195-1206.

Undetectable HCV RNA at Week 8

Detectable HCV RNA at Week 8

SVR

(%)

51 60

184 208

184 204

46 129

52 131

81 271

SVR for Early and Late Viral Responders With Boceprevir

31

ADVANCE

Poordad F. N Engl J Med. 2011; 364:1195-1206.

Undetectable HCV RNA at Week 8

Detectable HCV RNA at Week 8

SVR

(%)

51 60

184 208

184 204

46 129

52 131

81 271

61 % 18 %

Case study 2

• Week 12. – Side effects: fatigue. – Hb: 9 g/dL. – HCV RNA undetectable.

• How to manage anemia?

32

SPRINT-2

PR48 BOC/PR48

SVR

(%)

Hgb ≥10 g/dL

Hgb <10 g/dL

Hgb ≥10 g/dL

Hgb <10 g/dL

RESPOND-2

SVR

(%)

Hgb ≥10 g/dL

Hgb <10 g/dL

Hgb ≥10 g/dL

Hgb <10 g/dL

Sulkowski M et al , EASL 2011

20

50

25

76

0

20

40

60

80

100

31

58 56

73

0

20

40

60

80

100

77 246

60 108

212 263

263 363

12 60

83 165

5 20

119 157

Impact of Anemia on SVR

n/N = n/N =

Efficacy endpoints: EPO vs RBV dose reduction for managing anemia with boceprevir

*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort CI: confidence interval; EOT: end of treatment

Patie

nts (

%)

Δ (95% CI) –0.7% (–8.6, 7.2)*

178/249 178/251

Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559

RBV DR EPO • Secondary anemia management intervention was used in 18% of RBV DR patients

and in 37% of EPO patients

Case study 2

• Week 12. – Side effects: fatigue. – Hb: 9 g/dL. – HCV RNA undetectable – Ribavirin was reduced to 800 mg/gay

• What are the chances to achieve an SVR?

35

Higher SVR Rates if Undetectable HCV RNA Levels at Start Time of Primary Anemia

Management

Case Report 2

• Week 24. – Side effects: fatigue.

– HCV RNA: undetectable.

– What will be the duration of therapy?

37

Triple therapy with Boceprevir for Genotype 1 Treatment-Naive Patients

BOC + PegIFN + RBV

48 0 28 12 4

PegIFN + RBV

PegIFN + RBV

8 36

BOC + PegIFN + RBV

24

Early response*; stop at Wk 28; f/u 24 wks

F/u 24 wks

Boceprevir[1,2]

1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

SVR in Non-Black Patients with Undetectable HCV RNA Between Weeks 8-24

Column2

97 96

50

55

60

65

70

75

80

85

90

95

100

BOC RGT BOC/PR48

143 147

137 142

SVR

(%)

Case study 1

• Treatment stopped at Week 28.

• Follow-up 12-week and 24-week visits: HCV RNA: <25 IU undetectable.

40

Summary

• Anaemia is the main effect of Triple therapy with Boceprevir, peginterferon, and ribavirin

• Anaemia is associated with a higher SVR rates

• Anaemia can be managed by Ribavirin dose reduction without impacting SVR rates