Pretreatment assessment of Chronic Hepatitis C and Compensated Cirrhosis and Indications for Therapy

Teerha Piratvisuth MD.Prince of Songkla University

NGI <100 copies/ml

0

5

10

15

20

25

30

35

40

45

IFN-2b 24 wk IFN-2b 48 wk IFN-2b + Riba 24wk

IFN-2b + Riba 48wkSu

stai

ned

Vir

olog

ic R

espo

nse

6%

16%

33%

41%

McHutchison J. N Engl Med. 2000.

Treatment of chronic hepatitis C and response rates

Although all patients with chronic hepatitis C are potential candidates for antiviral therapy, careful pretreatment assessment and selection are mandatory to optimize the risk / benefit and cost / benefit ratio of therapy

Pretreatment Assessment• Determine the activity and stage of the liver disease• Evaluate symptoms and QoL modification attributable to

hepatitis C• Identify extrahepatic disease• Virological assessment : Genotype

: Viral load• Identify co-morbidities that can influence the treatment

decision• Identify contraindication to either Interferon or Ribavirin• Assess the motivation of the patients

Determine Activity and Stage of the Liver Disease

• Invasive : Liver Biopsy• Non-invasive

Afdhal NH. et al. Am J Gastroenterol. 2004; 44: 1160-73.

Liver Biopsy remains the gold standard for assessing liver disease in patients with chronic hepatitis C

Benefits Risks

Liver Biopsy in Chronic Viral Hepatitis

Patient’s consent Physician’s skill

Contraindications

Risk of Complications of Liver Biopsy

Severecomplication

0

10

20

30

Death

% 30%

0.3% 0.03%

Piccinino F. et al. J Hepatol. 1986;2:165-73

Poynard T. et al. Semin Liver Dis 2000;20:47-55

Pain

Pain after Liver Biopsy

0

10

20

30

40%40%

15%

Garcia G. et al. Am J Gastroenterology. 2001;96:3053-55

Would not agree to have biopsy if they know how they would feel during

and after the procedure

Pain extended beyond the day of the biopsy

Potential Limitations of Liver Biopsy

020406080

100%

10-20%

60-90%*

Fontana RJ. et al. Hepatology 2002;36:S57-S64

Underestimate of cirrhosis

Sampling error (multiple biopsies)

15-30%

Agreement for the stage of fibrosis

Dienstag JL. et al. Hepatology 2002;36:S152-S160

* Less agreement for the grade of inflammation

Liver Biopsy in 535 Patients with Chronic Viral Hepatitis

020406080

100%

3.7%

81%

Knowledge of grade and stage were considered

of value

Additional diagnosis

60%

Treatment was not changed

Andriulli A. et al. Dig Dis Sci 2001;46:1409-15

64%

Noninvasive methods and markers proposed for assessment of liver fibrosis

Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio

AST to platelet ratio (APRI) Forns fibrosis index Fibro Test Glycocirrhotest Hyaluronan Metalloproteinase Procollagen III European Liver Fibrosis (ELF) index FibroScan

AST / ALT Ratio: Diagnosis of Cirrhosis A Study of 252 patients with CH-C

Negative predictive values

86%

Positive predictive values

97%

Combined with platelet < 130 ×

109 / L

Specificity 97%Sensitivity 78%AST / ALT ratio > 1

Giannini E. et al. Arch Intern Med. 2003; 163: 218-24.

AST to Platelet Ratio Index (APRI)

57%

88%PPV

98%Cirrhosis

86%FibrosisIshak > 3

NPVCut-off value < 1.5

Wai CT. et al. Hepatology. 2003; 38(2): 512-26.

AST level ( /ULN)

Platelet count (10/L)× 100APRI =

Outline of initial reports of each major serum assay for hepatic fibrosis

Number of

patients

Name (serum markers)

Significant fibrosis

Cut-off

Sensiti-vity

Speci-ficity

PPV NPV

Indirect assaysWai et al. 2003

192 APRI(AST, platelets)

Ishak >3 < 1.5 41% 95% 88% 64%

Forns et al. 2002 476 Forns Index(age, GGT,

cholesterol, platelet count)

Metavir >2

< 4.2 94% 51% 40% 96%

Ziol et al. 2005 327 FibroScan(hepatic

elastography)

Metavir >2

> 8.7 56% 91% 88% 56%

Imbert-Bismut et al. 2001 134 FibroTest(α2-macroglobulin,α2-globulin, γ-globulin, apolipo-protein A1, GGTand total bilirubin)

Metavir >2

0.30 87% 59% 63% 85%

Castera et al. 2005 183 CombinedFibroScan and FibroTest

Metavir >2

NA NA NA NA

Outline of initial reports of each major serum assay for hepatic fibrosis

Number of patients

Name (serum markers)

Significant fibrosis

Cut-off

Sensiti-vity

Speci-ficity

PPV NPV

Indirect assaysPatel et al. 2004

402 FibroSpect(HA, TIMP-1 and α2-macroglobulin)

Metavir >2

0.36 77% 73% 74% 76%

Kelleher et al. 2005 95 SHASTA(HA, AST and

albumin)

Ishak >3 0.30 88% 72% 55% 94%

Rosenberg et al. 2004 1,021 ELF(Propeptide III

collagen, TIMP-1, HA )

Scheuer 3 or 4

0.102 90.5% 41% 99% 92%

HCV and Associated Conditions

• ESSENTIAL MIXED CRYOGLOBULINEMIA(EMC)

• GLOMERULONEPHRITIS

• LICHEN PLANUS

• SJOGREN’S SYNDROME

• PORPHYRIA CUTANEA TADA (PCT)

Identify extrahepatic disease

Evaluate Viral Factors

• HCV RNA Viral load• HCV Genotype• Co-infection - HBV

- HIV

Factors Predictive of Response to PEG IFN/RBV

• Viral– Genotype 2/3 – Viral load

Baseline <1.3 million IU/mL12 weeks = 0 or decrease >2 logs

• Host – Fibrosis F0–F1 estimated with Fibrotest– BMI <27

• Adherence: 80/80/80Poynard TM, et al. Submitted. 2002.

05

101520253035404550

Peg IFN α-2b monotherapy in CH-CSu

stai

ned

viro

logi

cal

resp

onse

(%)

14%

8%2%

38%

21%

42%47%

25%

36%

Genotype 2/3

ALL >2 m. <2 m.

62%

28%

6%

Genotype 1

ALL >2 m. <2 m.

Peg IFN α -2b 1.0 mcg/kg/wkIFN α -2b 3.0 MU TIW

Trepo C. et al. J Hepatol. 2000.

PEG-IFN SVR in Patients With HCV Genotype 1

0

10

20

30

40

50SVR (%)

29

51

4041

24 Weeks 48 Weeks

n = 101 n = 118 n = 250 n = 271

RBV800 mg/day

RBV1000/1200 mg/day

RBV800 mg/day

RBV1000/1200 mg/day

PEG-IFN 180 mcg qw

Hadziyannis SJ. EASL Annual Meeting. 2002.

24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3

0

20

40

60

80

100

All patients n = 224

Genotype 2 n = 42

Genotype 3 n = 182

SVR

81%93%

79%

Zeuzem S. et al. J Hepatol 2004; 40: 993-9

24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3

0

20

40

60

80

100

Genotype 2 < 600,000 IU/mL

n = 20

SVR 95%90.9%

69.9%

Zeuzem S. et al. J Hepatol 2004; 40: 993-9

85.9%

Genotype 2 > 600,000 IU/mL

n = 22

Genotype 3 < 600,000 IU/mL

n = 99

Genotype 3 > 600,000 IU/mL

n = 83

Evaluate Host Factors

• Alcohol drinking• BMI• Stage of liver disease• Iron load• Compliance

Zeuzem S. et al. Ann Intern Med 2004; 140: 370-81.Lonardo A. et al. Gastroenterology. 2004; 126: 586-97.

Adinolfi LE. et al. Hepatology. 2001; 33: 1358-64.Fargion S. et al. Am J Gastroenterol. 2002; 97: 1204-10.

Probability of developing cirrhosis

Marcellin F. et al. Hepatology. Nov 2002; 36(5) Suppl. 1: S47-S56.

Progression of fibrosis by duration of infection

Marcellin F. et al. Hepatology. Nov 2002; 36(5) Suppl. 1: S47-S56.

Effect of patient compliance on the rate of sustained virological response (>80% of treatment with 1.5

mcg/kg)Peg-IFN-alfa-2b + > 10.6 mg/kg Ribavirin

0 20 40 60 80 100

All patients

HCV Genotype 2, 3

Sustained virologic response %

63%

94%

72%

%

McHutchison J.

54%

HCV Genotype 1

HCV Genotype 1 and > 2million

copies/mL.

Contraindications to antiviral therapyAbsolute Relative

Decompensated (Child B-C) cirrhosis (outside the pretransplant setting)

Thyroid diseaseModerate depression Autoimmune markers

Sever portal hypertension (outside the pretransplant setting)

Alcohol and drug addiction Renal impairment (forpeginterferon alfa-2b)

Thrombocytopenia (<50,000) PsoriasisNeutropenia (<1,000)Severe depressionPsychosisSeizuresAutoimmune diseasePregnancyUncontrolled diabetesSevere systemic diseasesHypersensitivity to interferon α

Contraindications to antiviral therapy

Absolute RelativeAnemia (Hb < 10) Anemia (Hb < 12)Pregnancy HemoglobinopathyEnd-stage renal failure Severe iron overloadHemolytic anemiaIschemic heart diseaseIschemic vascular

Indications for anti-HCV Therapy

• Significant Liver Disease– fibrosis > F2– activity > A 2

• Significant sympotms: Fatigue Syndrome• Extrahepatic diseases

Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality

of life (HRQL) and fatigue

Author (ref.) Treatment Study size Additional scales (Significant differences

between SVRs and non-SVRs)

Bonkovsky 1999 ConsensusIFN / IFN-α2b

n = 437 Improvement in appetite, perception of health and sleep quality

Ware 1999 IFN-α2b / ribavirin n = 324 (IFN relapsers) Improvement in HCV-related health distress

McHutchison 2001 IFN-α2b / ribavirin n = 912 Improvements in work functioning and productivity

Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality

of life (HRQL) and fatigueAuthor (ref.) Treatment Study size Additional scales

(Significant differences

between SVRs and non-SVRs)

Roudot-Thoraval 2001

IFN-α2a n = 63 Non-significant trend to improvement in fatigue (VAS)

Bernstein 2002 PegIFN-α2a / IFN-α2a

n = 1,441 Improvement in the FSS

Rasenack 2002 PegIFN-α2a / IFN-α2a

n = 531 Improvement in the FSS

Cacoub 2002 Not recorded n = 355 Improvement in fatigue severity onlocal scale

Hassanein 2004 PegIFN-α2a / IFN-α2a /ribavirin

n = 1,221 Improvement in the FSS

Wright 2004 IFN-α2b / ribavirin n = 126 (histologically mild disease)

Rational for individualized care with Peg-Intron and Rebetol

Teerha Piratvisuth MD.Prince of Songkla University

Pretreatment assessment and individualized management of hepatitis C virus (HCV) patients

Treat without biopsy Biopsy to treat No biopsy No therapy

Young adults No co-factors

Easy-to-treat (HCV-2/3)No contraindications

Highly motivated Cirrhosis

Middle-aged HCV-1

High viral load Co-factors

Patient wants to know Doctor wants to know

Elderly/children contraindication

Long duration with “very low” ALT

Individualize in clinical practice

PEG-IFN SVR in Patients With HCV Genotype 1

0

10

20

30

40

50SVR (%)

29

51

4041

24 Weeks 48 Weeks

n = 101 n = 118 n = 250 n = 271

RBV800 mg/day

RBV1000/1200 mg/day

RBV800 mg/day

RBV1000/1200 mg/day

PEG-IFN 180 mcg qw

Hadziyannis SJ. EASL Annual Meeting. 2002.

24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3

0

20

40

60

80

100

Genotype 2 < 600,000 IU/mL

n = 20

SVR 95%90.9%

69.9%

Zeuzem S. et al. J Hepatol 2004; 40: 993-9

85.9%

Genotype 2 > 600,000 IU/mL

n = 22

Genotype 3 < 600,000 IU/mL

n = 99

Genotype 3 > 600,000 IU/mL

n = 83

Flat based dosing with IFN α-2b is associated with a decrease in SVR with increasing patient weight

IFN-alfa-2b 3 MU TIW 48 weeks

33%

19%13%

9%

0%

10%

20%

30%

40%

% S

usta

ined

vir

olog

ic r

espo

nse

McHutchison, JG. N Engl J Med. 1998;339:1485, Poynard T. Lancet. 1998;352:1426.

<55kg(n=40)

55-75kg (n=300)

75-95kg (n=334)

>95kg (n=132)

Patient weight

Distribution of patients by body weight

0

5

10

15

20

25

% o

f pat

ient

s

<60kg >60-70kg >70-80kg >80-90kg >90-100kg >100kg580-all

10.5 15.5 21.0 22.0 16.0 15.0

Manns, Lancet 2001, Data on file, Schering-Plough Corporation

Too little drug, to maximize

SVRToo much drug, increased side

effects

Appropriate amount of therapy

Peg-IFN-alfa-2b + ribavirinSustained Virologic Response by Weight

57%

48%41%

3MIU + riba1000-1,200mg

47%49% 46%

Peg 0.5 mcg/kg +riba1000-1,200mg

62%55%

49%

Peg 1.5 mcg/kg +riba 800mg

<65kg 65-85kg >85kg

Data on file, Schering-Plough Corporation

Effect of Ribavirin dose mg/kg on virologic response(Logistic regression analysis)

0%

20%

40%

60%

80%

100%

% S

usta

ined

vir

olog

ic r

espo

nse

5 7 9 11 13 15 17 19 21 23 25 27Ribavirin

PEG 0.5 mcg/kg

PEG 1.5 mcg/kg

Manns et al., Lancet 2001

Rebetol 10.6 mg/kg800mg for 75kg

Virologic Relapse

21

7

24

11

28

1417

7

-40

-30

-20

-10

0

% v

irolo

gic

rela

pse

Genotype 1 Genotype 2/3

Data on file Schering-Plough Corporation

Intron A+Rebetol

1,000-1,200 mg

PEG 1.5 +Rebetol800 mg

PEG 1.5 +Rebetol

<10.6 mg/kg

PEG 1.5 +Rebetol

>10.6 mg/kg

Sustained Virologic ResponseOptimal ribavirin Dosing

88%81%Genotype 2/3

48%34%Genotype 1

IFN-alfa-2b 3 MU Peg-IFN-alfa-2b 1.5

61%47%Overall

Optimal ribavirin >10.6 mg/kg

Effect of patient compliance on the rate of sustained virological response (>80% of treatment with 1.5

mcg/kg)Peg-IFN-alfa-2b + > 10.6 mg/kg Ribavirin

0 20 40 60 80 100

All patients

HCV Genotype 2, 3

Sustained virologic response %

63%

94%

72%

%

McHutchison J.

54%

HCV Genotype 1

HCV Genotype 1 and > 2million

copies/mL.

Rationale for Using Early Viral Response Endpoint

Drawbacks of Antiviral Therapy• Only half respond• Difficult to tolerate• Requires close monitoring • Expensive

Thus, identifying those with the greatest chance of benefiting (or not) from therapy is desirable

HCV RNA negative or > 2 log decrease at 12 weeks (n=380/478 with HCV RNA available; 79%)

SVR

(n=273/380; 72%)

SVR

(n=0/98)

NR

(n=107/380; 28%)

NR

(n=98/98; 100%)Davis GL. et al. Hepatology. Sep 2003; 38(3): 645-652.

Yes No

Early Virological Response

Cost Benefits of EVR

• If lack of EVR is used as the basis to stop treatment, 23% of cost of treatment saved versus no stopping– Genotype 1: 24-28% savings – Genotype 2 or 3: 0-5% savings – Savings similar to week 24 qualitative PCR

Genotype 2 or 3Genotype 2 or 3 Genotype 1 (and 4, 5 or 6)Genotype 1 (and 4, 5 or 6)

Liver biopsyLiver biopsy

HCV RNA detection at the end HCV RNA detection at the end of treatment and 24 weeks later of treatment and 24 weeks later

(lower limit of detection (lower limit of detection of the assay of the assay << 50 IU/50 IU/mLmL))

>>A2F2A2F2

EndEnd--ofof--treatment treatment virologicalvirological response response Sustained Sustained virologicalvirological responseresponse

HCV RNA quantification HCV RNA quantification at baseline and at week 12 at baseline and at week 12

(genotype 1)(genotype 1)

>> 2 log HCV RNA decrease or HCV RNA (2 log HCV RNA decrease or HCV RNA (--) ) at week 12at week 12

< 2 log HCV RNA < 2 log HCV RNA decrease at week 12decrease at week 12

Continue until week 48Continue until week 48 Stop treatment Stop treatment Enroll in trials of Enroll in trials of other therapiesother therapies

EndEnd--ofof--treatment treatment virologicalvirological response response Sustained Sustained virologicalvirological responseresponse

FollowFollow--up up without without

treatmenttreatment

<< A1F1A1F1

Peginterferon Peginterferon + ribavirin 800 mg + ribavirin 800 mg

24 weeks24 weeks

Peginterferon Peginterferon + ribavirin 1000+ ribavirin 1000--1200 mg 1200 mg

48 weeks48 weeks

HCV RNA detection at the end of treatment HCV RNA detection at the end of treatment and 24 weeks later (lower limit of detection and 24 weeks later (lower limit of detection

of the assay of the assay << 50 IU/50 IU/mLmL))

CHRONIC HEPATITIS CCHRONIC HEPATITIS C

HCV genotype determinationHCV genotype determination

Impact of IFN on Cirrhosis

Serfaty L. et al. Hepatology, 1998;27:1435

Cumulative ProbabilityAt 4 Years (%)

IFN No IFN P-Value

HCC 4.4 23 <0.001Decompensation 11 38 <0.001Survival 82 63 <0.001

Predictors of survival:IFN therapy, albumin >3.4 g/dL

Regression of Cirrhosis Following Treatment of Hepatitis C

Poynard T et al. Gastroenterology, 2002;122:1303

153

78

41 4641

50

20406080

100120140160

Before treatment After treatment

stage 4

stage 3

stage 2

stage 1

normal

Fibrosis stage Before and After Treatment With PEG-IFN α2b + RBV

No

of p

atie

nts

Reversion of cirrhosis 49%

Impaired Virological Response in CH-C Patients with Advanced Liver Disease

Gastroenteral. 2004;126:1015

0

10

20

30

40

50

Non-cirrhotic

23%

11 %

604 pts treated with IFN +/- Ribavirin

P < 0.001

Cirrhotic

SVR

Peg-IFN-α-2b plus Ribavirin Therapy in CH-C with Cirrhosis or Pre-Cirrhosis

0102030405060

SVR (%)

23%

Genotype 1(n=13)

Marrache F. et al. AASLD 2003

57%

43%

57%

33%

0%Genotype 2, 3

(n=15)Genotype 1

(n=14)Genotype 2, 3

(n=7)Relapses

(n=6)Non-responder

(n=19)

Peg-IFN-α-2b: 1.5 or/µg/kg weeklyRibavirin: 800-1200 mg daily

Previously IFN treated

Previously I/R treated

Naive

Histologic Benefit of PEG-IFN α monotherapyIn CH-C Patients with Advanced Fibrosis.

Everson G. et al. AASLD 2004

N = 184 patientsCirrhosis 76%

Extensive bridging fibrosis 24%

Table 1. Change from Baseline (post-base) for Fibrosis and Activity By subgroup

Subgroup Stage/Grade N Mean P-value

All Patients Fibrosis stage 184 -.4293 P<.0001Activity grage 184 -.1304 P=.0039

SVR Fibrosis stage 40 -1.000 P<.0001Activity grage 40 -.6500 P<.0001

Non-SVR Fibrosis stage 144 -.2708 P<.0001Activity grage 144 .0139 P=.7562

Liver biopsy: a median of 593 days apart

Peg-IFN / Ribavirin should always be considered in patients with child A cirrhosis

Contraindication : severe PHT with endoscopic signs of high risk for bleeding

: large splenomegaly with severe neutropenia and / or thrombocytopenia

Alberti A. Barcelona. 2005.