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Pretreatment assessment of Chronic Hepatitis C and Compensated Cirrhosis and Indications for Therapy. Teerha Piratvisuth MD. Prince of Songkla University. Treatment of chronic hepatitis C and response rates. 41%. NGI <100 copies/ml. 33%. 16%. Sustained Virologic Response.

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Teerha piratvisuth md prince of songkla university

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

Teerha Piratvisuth MD.

Prince of Songkla University


Teerha piratvisuth md prince of songkla university

Treatment of chronic hepatitis C and response rates

41%

NGI <100 copies/ml

33%

16%

Sustained Virologic Response

6%

McHutchison J. N Engl Med. 2000.


Teerha piratvisuth md prince of songkla university

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

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

Determine Activity and Stage of the Liver Disease

  • Invasive : Liver Biopsy

  • Non-invasive


Teerha piratvisuth md prince of songkla university

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

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


Teerha piratvisuth md prince of songkla university

Liver Biopsy in Chronic Viral Hepatitis

Benefits

Risks

Patient’s consent

Physician’s skill

Contraindications


Risk of complications of liver biopsy

Risk of Complications of Liver Biopsy

Severe

complication

30%

%

0.3%

0.03%

Pain

Death

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

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


Pain after liver biopsy

Pain after Liver Biopsy

40%

%

15%

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

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


Potential limitations of liver biopsy

Potential Limitations of Liver Biopsy

%

60-90%*

15-30%

10-20%

Underestimate of cirrhosis

Agreement for the stage of fibrosis

Sampling error (multiple biopsies)

* Less agreement for the grade of inflammation

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

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


Liver biopsy in 535 patients with chronic viral hepatitis

Liver Biopsy in 535 Patients with Chronic Viral Hepatitis

%

81%

64%

60%

3.7%

Knowledge of grade and stage were considered of value

Treatment was not changed

Additional diagnosis

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


Noninvasive methods and markers proposed for assessment of liver fibrosis

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

AST / ALT ratio > 1

Sensitivity 78%

Specificity 97%

Combined with platelet < 130  109 / L

Positive predictive values 97%

Negative predictive values 86%

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

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


Ast to platelet ratio index apri

AST to Platelet Ratio Index (APRI)

AST level ( /ULN)

 100

APRI =

Platelet count (10/L)

Cut-off value <1.5

PPV

NPV

Fibrosis

Ishak > 3

88%

86%

Cirrhosis

57%

98%

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


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

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


Outline of initial reports of each major serum assay for hepatic fibrosis1

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


Teerha piratvisuth md prince of songkla university

Identify extrahepatic disease

HCV and Associated Conditions

  • ESSENTIAL MIXED CRYOGLOBULINEMIA(EMC)

  • GLOMERULONEPHRITIS

  • LICHEN PLANUS

  • SJOGREN’S SYNDROME

  • PORPHYRIA CUTANEA TADA (PCT)


Evaluate viral factors

Evaluate Viral Factors

  • HCV RNA Viral load

  • HCV Genotype

  • Co-infection- HBV

    - HIV


Factors predictive of response to peg ifn rbv

Factors Predictive of Response to PEG IFN/RBV

  • Viral

    • Genotype 2/3

    • Viral load

      • Baseline <1.3 million IU/mL

      • 12 weeks = 0 or decrease >2 logs

  • Host

    • Fibrosis F0–F1 estimated with Fibrotest

    • BMI <27

  • Adherence: 80/80/80

Poynard TM, et al. Submitted. 2002.


Teerha piratvisuth md prince of songkla university

Peg IFN a-2b monotherapy in CH-C

Peg IFN a -2b 1.0 mcg/kg/wk

IFN a -2b 3.0 MU TIW

62%

47%

42%

38%

36%

28%

25%

Sustained virological response (%)

21%

14%

8%

6%

2%

<2 m.

<2 m.

ALL

>2 m.

ALL

>2 m.

Genotype 1

Genotype 2/3

Trepo C. et al. J Hepatol. 2000.


Teerha piratvisuth md prince of songkla university

PEG-IFN SVR in Patients With HCV Genotype 1

51

SVR (%)

41

40

29

n = 101

n = 118

n = 250

n = 271

PEG-IFN 180 mcg qw

RBV800 mg/day

RBV1000/1200 mg/day

RBV800 mg/day

RBV1000/1200 mg/day

24 Weeks

48 Weeks

Hadziyannis SJ. EASL Annual Meeting. 2002.


24 weeks peg ifn alfa 2b plus ribavirin treatment in hcv genotypes 2 or 3

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

SVR

93%

81%

79%

All patients n = 224

Genotype 2 n = 42

Genotype 3 n = 182

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


24 weeks peg ifn alfa 2b plus ribavirin treatment in hcv genotypes 2 or 31

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

SVR

95%

90.9%

85.9%

69.9%

Genotype 2 < 600,000 IU/mL n = 20

Genotype 2 > 600,000 IU/mL n = 22

Genotype 3 < 600,000 IU/mL n = 99

Genotype 3 > 600,000 IU/mL n = 83

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


Evaluate host factors

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

Probability of developing cirrhosis

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


Progression of fibrosis by duration of infection

Progression of fibrosis by duration of infection

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


Teerha piratvisuth md prince of songkla university

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

All patients

72%

HCV Genotype 2, 3

94%

HCV Genotype 1

63%

HCV Genotype 1 and > 2million copies/mL.

54%

%

Sustained virologic response %

McHutchison J.


Teerha piratvisuth md prince of songkla university

Contraindications to antiviral therapy


Teerha piratvisuth md prince of songkla university

Contraindications to antiviral therapy


Indications for anti hcv therapy

Indications for anti-HCV Therapy

  • Significant Liver Disease

    • fibrosis > F2

    • activity > A 2

  • Significant sympotms: Fatigue Syndrome

  • Extrahepatic diseases


Teerha piratvisuth md prince of songkla university

Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality of life (HRQL) and fatigue


Teerha piratvisuth md prince of songkla university

Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality of life (HRQL) and fatigue


Rational for individualized care with peg intron and rebetol

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

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

Treat without biopsy

Biopsy to treat

No biopsy No therapy

Individualize in clinical practice

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


Teerha piratvisuth md prince of songkla university

PEG-IFN SVR in Patients With HCV Genotype 1

51

SVR (%)

41

40

29

n = 101

n = 118

n = 250

n = 271

PEG-IFN 180 mcg qw

RBV800 mg/day

RBV1000/1200 mg/day

RBV800 mg/day

RBV1000/1200 mg/day

24 Weeks

48 Weeks

Hadziyannis SJ. EASL Annual Meeting. 2002.


24 weeks peg ifn alfa 2b plus ribavirin treatment in hcv genotypes 2 or 32

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

SVR

95%

90.9%

85.9%

69.9%

Genotype 2 < 600,000 IU/mL n = 20

Genotype 2 > 600,000 IU/mL n = 22

Genotype 3 < 600,000 IU/mL n = 99

Genotype 3 > 600,000 IU/mL n = 83

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


Teerha piratvisuth md prince of songkla university

Flat based dosing with IFN -2b is associated with a decrease in SVR with increasing patient weightIFN-alfa-2b3MU TIW 48 weeks

<55kg(n=40)

55-75kg (n=300)

75-95kg (n=334)

>95kg (n=132)

Patient weight

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


Distribution of patients by body weight

Distribution of patients by body weight

Appropriate amount

of therapy

Too little drug, to maximize SVR

Too much drug,

increased side effects

15.5

21.0

22.0

16.0

15.0

10.5

580-all

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


Peg ifn alfa 2b ribavirin sustained virologic response by weight

Peg-IFN-alfa-2b + ribavirin Sustained Virologic Response by Weight

<65kg

65-85kg

>85kg

62%

57%

55%

49%

49%

48%

47%

46%

41%

3MIU + riba

1000-1,200mg

Peg 0.5 mcg/kg +

Peg 1.5 mcg/kg +

riba1000-1,200mg

riba 800mg

Data on file, Schering-Plough Corporation


Effect of ribavirin dose mg kg on virologic response logistic regression analysis

PEG 0.5 mcg/kg

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

Rebetol 10.6 mg/kg

800mg for 75kg

PEG 1.5 mcg/kg

Ribavirin

Manns et al., Lancet 2001


Virologic relapse

Virologic Relapse

Intron A+Rebetol 1,000-1,200 mg

PEG 1.5 +Rebetol 800 mg

PEG 1.5 +Rebetol <10.6 mg/kg

PEG 1.5 +Rebetol >10.6 mg/kg

Data on file Schering-Plough Corporation


Sustained virologic response optimal ribavirin dosing

Sustained Virologic ResponseOptimal ribavirin Dosing

Optimal ribavirin >10.6 mg/kg

Peg-IFN-alfa-2b 1.5

IFN-alfa-2b 3 MU

Overall

47%

61%

Genotype 1

34%

48%

Genotype 2/3

81%

88%


Early virological response

Early Virological Response

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

Yes

No

SVR

(n=273/380; 72%)

SVR

(n=0/98)

NR

(n=98/98; 100%)

NR

(n=107/380; 28%)

Davis GL. et al. Hepatology. Sep 2003; 38(3): 645-652.


Cost benefits of evr

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


Teerha piratvisuth md prince of songkla university

CHRONIC HEPATITIS C

HCV genotype determination

Genotype 2 or 3

Genotype 1 (and 4, 5 or 6)

Peginterferon + ribavirin 800 mg 24 weeks

Liver biopsy

>A2F2

< A1F1

HCV RNA detection at the end of treatment and 24 weeks later (lower limit of detection of the assay < 50 IU/mL)

Peginterferon + ribavirin 1000-1200 mg 48 weeks

Follow-up without treatment

HCV RNA quantification at baseline and at week 12 (genotype 1)

End-of-treatment virological response Sustained virological response

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

< 2 log HCV RNA decrease at week 12

Continue until week 48

Stop treatment Enroll in trials of other therapies

HCV RNA detection at the end of treatment and 24 weeks later (lower limit of detection of the assay < 50 IU/mL)

End-of-treatment virological response Sustained virological response


Impact of ifn on cirrhosis

Impact of IFN on Cirrhosis

IFN No IFN P-Value

HCC 4.4 23 <0.001

Decompensation 11 38 <0.001

Survival 82 63 <0.001

Cumulative Probability

At 4 Years (%)

Predictors of survival:

IFN therapy, albumin >3.4 g/dL

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


Regression of cirrhosis following treatment of hepatitis c

Regression of Cirrhosis Following Treatment of Hepatitis C

Fibrosis stage Before and After Treatment With

PEG-IFN 2b + RBV

Reversion of cirrhosis 49%

No of patients

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


Impaired virological response in ch c patients with advanced liver disease

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

SVR

604 pts treated with IFN +/- Ribavirin

P < 0.001

23%

11 %

Cirrhotic

Non-cirrhotic

Gastroenteral. 2004;126:1015


Peg ifn 2b plus ribavirin therapy in ch c with cirrhosis or pre cirrhosis

Peg-IFN--2b: 1.5 or/g/kg weekly

Ribavirin: 800-1200 mg daily

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

SVR (%)

57%

57%

43%

33%

23%

0%

Non-responder

(n=19)

Genotype 1

(n=14)

Genotype 2, 3

(n=7)

Relapses

(n=6)

Genotype 2, 3

(n=15)

Genotype 1

(n=13)

Naive

Previously IFN treated

Previously I/R treated

Marrache F. et al. AASLD 2003


Histologic benefit of peg ifn monotherapy in ch c patients with advanced fibrosis

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

SubgroupStage/GradeNMeanP-value

All PatientsFibrosis stage184-.4293P<.0001

Activity grage184-.1304P=.0039

SVRFibrosis stage40-1.000P<.0001

Activity grage40-.6500P<.0001

Non-SVRFibrosis stage144-.2708P<.0001

Activity grage144.0139P=.7562

Histologic Benefit of PEG-IFN  monotherapyIn CH-CPatients with Advanced Fibrosis.

Cirrhosis 76%

N = 184 patients

Extensive bridging fibrosis 24%

Liver biopsy: a median of 593 days apart

Everson G. et al. AASLD 2004


Peg ifn ribavirin should always be considered in patients with child a cirrhosis

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.


Teerha piratvisuth md prince of songkla university

THANKYOU


Teerha piratvisuth md prince of songkla university

THANKYOU


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