Alessio AghemoFirst Division of GastroenterologyFondazione IRCCS Ca’ Granda, Ospedale Maggiore PoliclinicoUniversità degli Studi di Milano

5th Paris Hepatitis C Conference

Paris, 30 January 2012

Luncheon: How to optimize treatment of G2 and G3 patients

HCV infection (genotype 2a/c) known since 1998

No risk factors for HCV ALT values 2 x ULN since 1998Comorbidities: overweight (BMI 28)

September 2008:Fibroscan 10.2 KPa, SR 96%, IQR 1.1Enlarged liver at US, no splenomegalyRefuses PegIFN plus Rbv

Continues Follow-up visits at our center

S.G. 57 yr Housewife

• ALT IU/L 61• HCV-RNA 105/IU/mL 2.68

• Total Bilirubin mg/dL 1.2• Albumin g/dL 4.1• Prothrombin ratio 1.12• Platelets 103/mmc 195

• Fibroscan KPa 10.2

1125.62

1.03.9

1.11196

9.8

783.62

1.04.0

1.16184

11.4

Sep 2008 Sep 2010Sep 2009

Liver Function Tests

Liver Function

Liver biopsy: 24 mm specimen Chronic hepatitis with septae (Ishak G7, S4)

• ALT IU/L 78• HCV-RNA 105/IU/mL 3.68

• Total Bilirubin mg/dL 1.0• Albumin g/dL 4.1• Prothrombin ratio 1.12• Platelets 103/mmc 195

• Hb 14• WBC 5500• Neutrophils 2900

33<12

1.03.9

1.11127

12.541301630

39ND

0.93.9

1.16118

11.835001450

Baseline Week 4Week 2

Liver Function Tests During PegIFNalfa2a 180 mcg

+ Rbv 800 mg/day

Liver Function

What is the optimal treatment duration?

HCV RNA Kinetics During PegIFN + Rbv to Predict Treatment Outcome and Individualize Treatment Duration

HCV-2/3 Patients

Weeks 0 12-16 24

PegIFNalfa + RBV 800/dayPegIFNalfa + RBV 800 mg/day

Design No. Regimen Duration RVR (LOD)

Allocation by RVR

Dalgard 2004 122 Peg2b + Rbv wbd 14 w 78% (50 IU)

Mangia 2005 283 Peg2b 1.0 + Rbv wbd 12 w 63% (50 IU)

Randomization by RVR

von Wagner 2005 153 Peg2a + Rbv wbd 16 w 93% (600 IU)

Dalgard 2008 428 Peg2b + Rbv wbd 14 w 71% (50 IU)

Baseline Randomization

Shiffman 2007 1469 Peg2a + Rbv 800 mg 16 w 65% (50 IU)

Lagging 2008 382 Peg2a + Rbv 800 mg 12 w 60% (15 IU)

SVR Rates Following Abbreviated Therapy in HCV-2 and HCV-3

RVR (+) RVR (-)

50%

67%

-

75%

RVR (+)

Standard (24 weeks)Abbreviated (12-16 weeks)

91%

87%

95%

93%

-

89%

95%

97%

HCV-2 only

65% 65%82%

71%

0%

20%

40%

60%

80%

100%

Genotype 2 Genotype 3

16 weeks Pegasys 180 ug + Copegus 800 mg24 weeks Pegasys 180 ug + Copegus 800 mg

The ACCELERATE Study: SVR Rates by GenotypeS

VR

(%

)

Standard population; VR = HCV RNA < 50 IU/mL

N=346 N=303 N=333 N=327

P= <.0001 P= 0.1565

60%

70%77%

86%

60%

70%

66%

76%

White lines represent 95% confidence intervals

Shiffman ML et al NEJM 2007 Jul 12;357(2):124-34.

The ACCELERATE Study: sub-analysis of SVR in Patients with RVR

N=215

SVRSVR

p=0.0012

p=0.1046

92%

90%

81%

84%

0% 20% 40% 60% 80% 100%

Genotype 3

Genotype 2

16 weeks Pegasys 180 ug + Copegus 800 mg

24 weeks Pegasys 180 ug + Copegus 800 mg

N=243

N=212

N=193

Shiffman ML et al NEJM 2007 Jul 12;357(2):124-34.

Identifying HCV-2/3 Patients Who Can Receive a 16-wk Abbreviated Course of PegIFNalfa2a and Ribavirin

Similar SVR rates 87% vs 88% in patients with at least 2 positive predictors LVL, <40 yrs, <65 Kg and absence of cirrhosis

Diago M et al, Hepatology 2010 ; 51(6):1897-903

Efficacy of PegIFNalfa2a plus Rbv in 818 HCV-2 & HCV-3 Patients with Advanced Fibrosis and Cirrhosis

EOT SVR Rel

100

80

60

40

20

0

89 86 84

61

76

57

15

2832

Res

po

nse

rat

es (

%)

Without advanced fibrosis

Bridging fibrosis (no cirrhosis)

Cirrhosis

Bruno S et al, Hepatology 2010, 51(2):388-97

High Rates of Post-treatment Relapse in HCV-2 and 3 Patients with Advanced Fibrosis

PegIFNalfa2a + Rbv 800 mg PegIFNalfa2b + Rbv 800-1200 mg

Prati GM et al, J Hepatology 2012, 56:341-347

High Rates of Post-treatment Relapse in HCV-2 and 3 Patients with Advanced Fibrosis

Prati GM et al, J Hepatology 2012, 56:341-347

• ALT IU/L 39• HCV-RNA 105/IU/mL ND

• Total Bilirubin mg/dL 0.9• Albumin g/dL 3.9• Prothrombin ratio 1.16• Platelets 103/mmc 118

• Hb 11.8• WBC 3500• Neutrophils 1450

55ND

1.03.9

1.11147

11.541301630

573.62

0.93.9

1.16198

13.855002450

Week 4 Week 4 fupWeek 24 (EOT)

Liver Function Tests During PegIFNalfa2a 180 mcg

+ Rbv 800 mg/day anf Follow-up

Liver Function

What Now???

Retreat with PegIFN plus Rbv?

Retreat using high dose Rbv? (Off Label)

Retreat using Telaprevir? (Off Label)

Wait for new drugs? (2014-

2015)

Telaprevir Alone or in Combination With PegIFN/Rbv For HCV-2 Patients

Foster GR et al, Gastroenterology 2011, 141:881-889

Phase II study on 23 HCV-2 and 26 HCV-3 patients