Quali sono i limiti dell’attuale terapia

Terapia dell’epatite C tra passato e futuro

Alessandro GrassoS.C. Medicina Interna e

GastroenterologiaOsp. San Paolo Savona

PegIFN alfa-2b

0.5 + RBV800

SVR Rates by HCV Treatment Drug Combination and Dose

1. Manns MP, et al. Lancet. 2001 2. Fried MW, et al. N Engl J Med. 2002.

100

80

60

40

20

0

SVR

(%)

IFN + RBV

PegIFN alfa-2b 1.5

+ RBV800

IFN + RBV

PegIFN alfa-2a

PegIFN alfa-2a +

RBV1000-1200

Manns et al[1] Fried et al[2]

47 4754*

4456†

29

n = 505 514 800 224 444 453n =

*P = .01 vs both arms, †P = .001 vs both arms

2011Almost 50% of

patients do not respond to treatment

DISEASE RELATED

Genotype 1 (1)

High viral load (1)

Cirrhosis/bridging fibrosis (1)

Steatosis (1)

Factors associated with a reduction of SVR rate with PegIFN + RBV

1) Dienstag JL et al. Gastroenterology 2006; 2) Manns MP et al. Lancet 2001; 3) Bain VG et al. Aliment Pharmacol Ther 2008; 4) Hadziyannis SJ et al. Ann Intern Med 2004; 5) Hanouneh IA et al Clin Gastroenterol Hepatol 2008;

6) Backus LI et al. Hepatology. 2007; 7) Pol S et al. Expert Opin Biol Ther 2006; 8) Ge D et al. Nature 2009; 9) Falck-Y et al. Ann Intern Med 2002

PATIENTS RELATED

Age > 40 years (1)

Male sex (2)

Afro-american race (1)

Increased BMI (1)Metabolic Syndr – Diabetes (2)

Immunosuppression (3)

Alcool (4)

Genetic polimorphysm (5)

TREATMENT RELATED

Aderence (1)

Duration and schedule (6-8)

Dose reduction (9)

Controindications (7)

Outline

Impact of viral, host and genetic factors on SVR

Adherence to antiviral treatment

Outline

Impact of viral, host and genetic factors on SVR

Adherence to antiviral treatment

Overall GT 1 GT 2/3

SVR With PegIFN and Ribavirin according with genotype

PegIFN alfa-2b 1.5 µg/kg/week +

RBV 800 mg/day for 48 weeks[1]

PegIFN alfa-2a 180 µg/week + weight-based RBV (1000 or

1200 mg/day) for 48 weeks[2]

Manns M, et al. Lancet. 2001

42

82

100

80

60

40

20

0

54

SV

R (

%)

n = 348 n = 163n = 511

46

76

56

Overall GT 1 GT 2/3n = 298 n = 140n = 453

Fried MW, et al. N Engl J Med. 2002

N = 96 144 99 153 34 47 33 48 62 97 66 105N =101 118 250 271 51 71 60 85 50 47 190 186

SVR Rates by HCV Treatment Duration Genotype, and Baseline HCV RNA

Hadziyannis SJ, et al. Ann Intern Med. 2004

Genotype 2/3Genotype 1

100

80

60

40

20

0

Pat

ien

ts (

%)

AllPatients

Low HCV RNA

High HCV RNA

24w Low Dose 24w Standard Dose

29

42 41

5241

52 5565

1626

3647

100

80

60

40

20

0P

atie

nts

(%

)

AllPatients

Low HCV RNA

High HCV RNA

84 81 79 8085 83 88

7784 80

7482

48w Low Dose 48w Standard Dose

Hadziyannis SJ, et al. Ann Intern Med. 2004.

SVR at End of Follow-up24 wks of RBV 800 mg/day + pegIFN alfa-2a24 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a48 wks of RBV 800 mg/day + pegIFN alfa-2a48 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a

26 26 28

41

75 7470 73

29

46 45

57

87 84 81 83100

80

60

40

20

0

Pat

ien

ts (

%)

Advanced Fibrosis Minimal Fibrosis

Genotype 1 Genotype 2/3 Genotype 1 Genotype 2/3

SVR With PegIFN and Ribavirin according with genotype and stage

of Fibrosis

On-treatment Viral Response and Outcome

*Subset of Nonresponse

7

6

5

4

3

2

1

00-2-4-8 4 8 12 16 20 24 32 40 48 52 60 72

Wks After Start of Therapy

HC

V R

NA

(lo

g10

IU/m

L)

Undetectable

RVR EVR ETR SVR

Relapse

Partial Response*

Null Response*

PegIFN alfa and RBV

Ghany MG, et al. Hepatology. 2009 on behalf of American Association for the Study of Liver Diseases

Slow Response

PPV for SVR in genotype 1 HCV

•RVR 75-90%•EVR 50%•Slow responders 20-30%

DVR

82 80

16 Wks (n = 71)

24 Wks (n = 71)

7985*

16 Wks (n = 733)

24 Wks (n = 732)

SVR

(%)

SVR

(%)

1. Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Shiffman M, et al. N Engl J Med. 2007;357:124-134.

Comparing Treatment Durations in GT 2/3 Patients Achieving RVR

*P = .002 vs 16 wks.

0

20

40

60

80

100

0

20

40

60

80

100

Von Wagner et al[1]

Shiffman et al[2]

PegIFN α-2a 180 µg/wk + WB RBV

RVR16 wks total

24 wks total

PegIFN α-2a180 µg/wk + RBV 800 mg/day

RVR16 wks total

24 wks total

Extending Therapy in Treatment-Naive Genotype 1 HCV Pts With

Slow Response

SVRRelapse

0

20

40

60

80

100

48 Wks(n = 165)

72 Wks(n = 161)

Patie

nts

(%)

18

3859

20

1. Pearlman BL, et al. Hepatology. 20007 2. Buti M, et al. EASL 2010

Higher SVR rate with 72 vs 48 wks of treatment in slow responders*[1]

– Dose reductions, discontinuations similar

PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day

48 wks total

72 wks totalSlow responders

SUCCESS study had same study design and showed no overall benefit[2]

p=0.03

p=0.004

Response-guided therapy in patients with genotype 1 (applies also to genotype 4 at a B2 grade of evidence)

J Hepatol 2011*LVL Y<400,000-800,000 IU/ml

J Hepatol 2011

Response-guided therapy in patients with genotype 2 and 3

Retreatment of PegIFN/RBV Relapsers

1. McHutchison JG, et al. N Engl J Med. 2010 2. Poynard T, et al. Gastroenterology. 2009

PegIFN alfa-2a/RBV for 48 Wks

in PegIFN/RBV Relapsers

33

PegIFN alfa-2b/RBV for 48 Wks

in PegIFN/RBV Relapsers

20

McHutchison et al[1]

SV

R (

%)

0

20

40

60

80

100

SV

R (

%)

0

20

40

60

80

100

EPIC3[2]

1. Jensen D, et al. Ann Intern Med. 2009 2. Poynard T, et al. Gastroenterology. 20093. Bacon BR, et al. Hepatology. 2009

8.0

PegIFN alfa-2a/RBV for 48 Wks in

PegIFN alfa-2b/RBV Nonresponders

SV

R (

%)

0

20

40

60

80

100

6.3

PegIFN alfa-2b/RBV for 48 Wks in PegIFN/RBV

Nonresponders

SV

R (

%)

0

20

40

60

80

100

10.7

cIFN for 48 Wksin PegIFN/RBV Nonresponders

SV

R (

%)

0

20

40

60

80

100

REPEAT[1] EPIC3[2] DIRECT[3]

Retreatment of PegIFN/RBV Nonresponders Yields Low SVR Rates

REPEAT: 72-Week Treatment Duration Associated With Higher SVR Rate

Pooled 72 weeks (n = 473) vs 48 weeks (n = 469)

16

8

72 Weeks(360/180 µg and 180 µg)

48 Weeks(360/180 µg and 180 µg)

SV

R (

%)

0

20

40

P = .0006

Modified ITT*

Patients with chronic HCV infection not responsive to pegIFN alfa-2b/ RBV therapy

n=417 n=469

Jensen D, et al. Ann Intern Med. 2009.

Thompson AJ, et al. Gastroenterology 2010.

Predictor Adjusted Odds Ratio (95% CI) P Value

rs12979860 CC 5.2 (4.1-6.7) < .0001

HCV RNA level ≤ 600,000 IU/mL 3.1 (2.3-4.1) < .0001

White vs black 2.8 (2.0-4.0) < .0001

Hispanic vs black 2.1 (1.3-3.6) .0041

METAVIR F0-F2 2.7 (1.8-4.0) < .0001

Fasting blood sugar < 5.6 mmol/L 1.7 (1.3-2.2) < .0001

•ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level (n = 1604) plus 67 patients from another trial

Multivariate Analysis of Baseline Predictors of SVR (Genotype 1 HCV)

A genome-wide association study of more than 1,600 individuals identified that a polymorphism on chromosome 19, rs12979860, is strongly associated with SVR

The polymorphism resides 3 kilobases (kb) upstream of the IL28B gene encoding IFN-λ-3

Neumann AU, et al. J Hepatol 2010 Thompson AJ, et al. Gastroenterology 2010.

Interleukin-28B polymorphism is associated with rapid virological response in genotype 1 HCV patients

High body mass index is an independent risk factor for nonresponse to antiviral

treatment in chronic hepatitis C Retrospective analysis of all patients at a single center with chronic

hepatitis C treated with antiviral medication from 1989 to 2000 A total of 253 patients were treated with either IFN monotherapy (either

standard or pegylated) or IFN-2b in combination with ribavirin.

Bressler BL,et al. Hepatology 2003

Insulin-resistance and SVR in HCV G1 patients

33

61

0

20

40

60

80

100

SVR

(%)

HOMA-IR > 2 HOMA-IR<2

Romero-Gomez M, et al. Gastroenterology. 2005

P = .007

159 patients with chronic hepatitis C (113 G1; 46 non-G1) treated with PegIFN + RBV

Genotype , HOMA-IR and fibrosis were independently associated with SVR

Impact of insulin resistance on sustained response in HCV patients treated with pegylated

interferon and ribavirin: A meta-analysis

Deltenre P. et al. J Hepatol 2011

Outline

Impact of viral, host and genetic factors on SVR

Adherence to antiviral treatment

Many factors associated with poor Adherence to PegIFN and Ribavirin

Adherence

Psychological comorbidities

Injection Drug Use

Adverse events of

medication

Inadequate follow-up

Patient’s lack of belief in

treatment benefit

Poor relationship between the patient and

provider

Treatment complexity

Depression

Impact of HCV Infection on Quality of Life

Foster G, et al. Hepatology. 1998.

Controls HCV positive

P < .01 for all comparisons between control and HCV positive

SF

36 S

core

0

20

40

60

80

100

Physica

l Functi

oning

Socia

l Functi

oning

RL: Physi

cal

RL: Emotional

Mental H

ealth

Energy/Fa

tigue

Pain

Health Perce

ption

7993

66

91

57

91

60

86

59

75

48

64 7386

53

79

Common Adverse Events Associated With PegIFN/RBV Therapy

• Influenza like (fatigue, headache, fever, and rigors): > 50%

• Psychiatric (depression, irritability, and insomnia): 22% to 31%

• Neutropenia (ANC < 1500/mm3): 18% to 20%[1,2] – Severe neutropenia* (ANC < 500/mm3): 4%– Serious infections are uncommon and G-CSF is rarely necessary[3]

• Anemia (Hb < 12 g/dL): ~ 30%[1,2]

– Nadir within 6-8 wks– Severe anemia† (Hb < 10 g/dL): 9% to 15%

• Laboratory abnormalities are the most common reasons for HCV therapy dose reduction

Manns MP, et al. Lancet. 2001 Fried MW, et al. N Engl J Med. 2002. Soza A, et al. Hepatology. 2002.

*And treatment discontinuation.†And dose modification.

Months

Inci

denc

e/Se

verit

y

Depression

Fatigue

Influenza-like symptoms

Time Course of Treatment-Associated Psychiatric Adverse Effects

Anxiety

1 2 3 400

20

40

60

80

100

Dan A, et al. J Hepatol. 2006

Constant A, et al. J Clin Psychiatry 2005

Genotype 1 Genotype 2 and 30

10

20

30

40

50

60

70

80

90

100

42

82

51

90

34

89

0-034

0-011

SVR according with Adherence to combination therapy in G1 chronic

hepatitis C

McHutchison JC, et al. Gastroenterology 2002

Analysis in a subgroup of 511 patients treated with Peginterferon alfa 2b plus ribavirin

SV

R %

Wave 1 (2011-2014): add-on Tx 1° generation DDAs + SOC: naive and experienced -Naives: consider empiric Tx -Experienced: offer Tx (particularly relapser) -Nulls: stratify by stage

Wave 2 (2014-2016): the better mousetrap Substitution of 2° generation DAAs, nucs Substitution of better tolerated IFNs 4 drug regimen for P/R/DAA failure

Wave 3 (2016-2020): the holy grail Oral cocktails of DAAs, host cofactor

inhibitor, RBV Many roads to the same destination!

The new waves of HCV therapy

2001-2011 PegInterferon plus Ribavirin

> 90% cure of G1 with oral pills with no side effects